Pharmacokinetic and Pharmacodynamic Markers of Mycophenolic Acid Associated with Effective Prophylaxis for Acute Graft-Versus-Host Disease and Neutrophil Engraftment in Cord Blood Transplant Patients.
Yoshimura Kazuaki,Yano Ikuko,Yamamoto Takashi,Kondo Tadakazu,Kawanishi Misaki,Isomoto Yui,Yonezawa Atsushi,Takaori-Kondo Akifumi,Matsubara Kazuo
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is frequently used to prevent acute graft-versus-host disease (aGVHD) in patients receiving hematopoietic stem cell transplantation (HSCT). However, optimal doses of MMF and target MPA concentrations in HSCT patients have not been defined. In this study, relationships between pharmacokinetic or pharmacodynamic markers of MPA and successful aGVHD prevention and neutrophil engraftment were evaluated to inform individualized MPA treatments in HSCT patients. We recruited 35 patients undergoing cord blood transplantation (CBT) who were treated with MMF. Area under the concentration-time curves from 0 to 24 hours (AUC) for free MPA and MPA acyl glucuronide (AcMPAG) at 1 week after the start of MMF treatments were significantly higher in patients with gastrointestinal (GI) aGVHD at stage ≥I than those at stage 0. Patients with faster neutrophil engraftment had higher free MPA AUC at 1 week after the start of MMF treatments compared with those with slower neutrophil engraftment. Inosine-5'-monophosphate dehydrogenase activity in peripheral blood mononuclear cells and single nucleotide polymorphisms in genes that were previously associated with MPA pharmacokinetics and pharmacodynamics were not an independent predictor for the clinical outcomes. Receiver-operating characteristic model analyses showed that cutoff values of AUC for successful GI aGVHD prevention were .689 and 15.6 µg⋅hour⋅mL for free MPA and AcMPAG, respectively. In addition, the cut-off value of free MPA AUC for neutrophil engraftment by day 25 was .405 µg⋅hour⋅mL. In conclusion, free MPA AUC may be a better predictor of the prevention of GI aGVHD and neutrophil engraftment compared with that of total MPA in patients receiving CBT. Hence, monitoring of the free MPA AUC between .405 and .689 µg⋅hour⋅mL could be considered informative of individualized MPA treatments in CBT patients.
Influence of uridine diphosphate-glucuronosyltransferases (1A9) polymorphisms on mycophenolic acid pharmacokinetics in patients with renal transplant.
Ciftci H S,Demir E,Karadeniz M S,Tefik T,Nane I,Oguz F S,Aydin F,Turkmen A
BACKGROUND:There are differences in pharmacokinetic of mycophenolic acid among individuals. The UGT1A9 enzyme is of special interest since it is the main enzyme involved in the glucuronidation of MPA. Single nucleotide polymorphisms in the UGT1A9 gene may be responsible for individual differences in the pharmacokinetics of MPA. The aim of this study was to explain MPA pharmacokinetics in UGT1A9 1399 C > T polymorphisms in Turkish renal transplant patients. PATIENTS AND METHODS:One hundred and twenty-five living-donor transplant recipients and 100 healthy control subjects underwent UGT1A9 1399 C > T genotyping using polymerase chain reaction-restriction fragment length polymorphism. Concentrations of MPA were determined with Cloned Enzyme Donor Immunoassay (CEDIA). Besides that, all the patients were monitored for acute rejection and graft function during the study period. RESULTS:The UGT1A9 1399 C > T CC, CT, and TT genotype frequencies among patients were, respectively, 68.0%, 23.2%, and 8.8%. The CC, CT, and TT genotype frequencies among controls were, respectively, 63.0%, 23.0%, and 14.0%. There was no significant difference between patients and controls (p = .480, p = .999, p = .286, respectively). At first month, respectively, through blood concentrations of MPA were significantly higher in UGT1A9 1399 C > T TT carriers than in CT and CC carriers (p = .046). The doses for these patients were lower at first month (p = .021). Acute rejection episodes were not associated with the CC vs CT or TT genotypes (p = .064). CONCLUSIONS:Our results demonstrated a correlation between the UGT1A9 1399 C > T polymorphism and MPA pharmacokinetics among renal transplant patients. Determination of UGT1A9 polymorphism may help to achieve target of MPA blood concentrations.
Pharmacokinetics and pharmacogenomics of mycophenolic acid and its clinical correlations in maintenance immunosuppression for lupus nephritis.
Yap Desmond Y H,Tam Chun Hay,Yung Susan,Wong Sunny,Tang Colin S O,Mok Temy M Y,Yuen Catherine K Y,Ma Maggie K M,Lau Chak Sing,Chan Tak Mao
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
BACKGROUND:There is little data on mycophenolic acid (MPA) pharmacokinetics and pharmacogenomics and optimal MPA exposure in lupus nephritis (LN) patients during long-term maintenance. METHODS:We measured blood MPA levels at 1, 2, 4, 8, 10 and 12-h post-dose (i.e. C1, C2, C4, C8, C10 and C12) in 88 stable LN patients receiving maintenance prednisolone and mycophenolate mofetil, repeated every 6 months. The relationship between MPA exposure and single nucleotide polymorphisms (SNPs) of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2; rs2273697, rs3740066, rs717620 and rs17222723), organic anion-transporting polypeptides (OATPs; rs7311358 and rs4149117) and uridine diphosphate glucuronosyltransferase (UGT; rs17863762, rs6714486, rs17868320 and rs72551330) was also investigated. RESULTS:C1, C2 and C12 were 8.3 ± 6.6 , 7.2 ± 5.2 and 2.0 ± 1.4 mg/L and all correlated with the 12-h area under the curve (AUC0-12; r = 0.51, 0.85 and 0.73; P = 0.02, <0.001 and <0.001, respectively). C12 inversely correlated with hemoglobin, immunoglobulins and leukocyte levels (P < 0.05 for all). Five renal flares, 11 episodes of infection and 10 episodes of anemia (hemoglobin <10 g/dL) occurred over 96 weeks, with a corresponding C12 of 1.3 ± 0.5, 4.3 ± 2.6 and 2.9 ± 1.5 mg/L, respectively (versus 2.4 ± 1.2, 1.8 ± 1.2 and 1.7 ± 1.1 mg/L in patients without these complications; P = 0.041, <0.001 and 0.004). SNP rs2273697 A/G in the ABCC2 gene was associated with lower MPA exposure compared with G/G (1075.9 ± 239.9 versus 1891.5 ± 918.9 mgh/L per g/kg; P = 0.003). SNPs of OATP and UGT were unrelated to MPA level. CONCLUSION:MPA C12 correlates with the AUC0-12 and is related to renal flare, infection and anemia. SNP rs2273697 A/G is associated with lower MPA exposure.
Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid.
Tague Laneshia K,Byers Derek E,Hachem Ramsey,Kreisel Daniel,Krupnick Alexander S,Kulkarni Hrishikesh S,Chen Catherine,Huang Howard J,Gelman Andrew
The pharmacogenomics journal
Single-nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was 1-year survival. Secondary outcomes were 3-year survival, nonminimal (≥A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan-Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased 1-year survival [rs7311358 HR 7.76 (1.37-44.04), p = 0.021; rs4149117 HR 7.28 (1.27-41.78), p = 0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01 (1.06-3.81), p = 0.031; rs7311358 GG699/G699A: OR 2.18 (1.13-4.21) p = 0.019] and lower survival through 3 years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p = 0.048, rs7311358 p = 0.023). For the MPA patients, Cox regression modeling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.
Ca-Calcineurin Axis-Controlled NFAT Nuclear Translocation Is Crucial for Optimal T Cell Immunity in an Early Vertebrate.
Wei Xiumei,Li Huiying,Zhang Yu,Li Cheng,Li Kang,Ai Kete,Yang Jialong
Journal of immunology (Baltimore, Md. : 1950)
Calcium ion (Ca) is a widespread and primitive second messenger that regulates physiological cell functions in almost all life beings. Ca influx-induced NFAT activation is essential for T cell function and adaptive immunity. However, whether and how Ca signaling modulates T cell immunity in early vertebrates, especially in nontetrapods, remains largely unknown. To address these questions, a Nile tilapia () model was employed to investigate the regulation of ancestral T cell immunity by Ca-NFAT signaling in jawed fish. In Nile tilapia, an evolutionarily conserved Ca-NFAT signaling pathway is involved in the primary adaptive immune response during infection. Meanwhile, T cell signals trigger several events along the Ca-NFAT axis in this early vertebrate, including Ca influx, calcineurin activation, and NFAT nuclear import. More critically, suppression of Ca-NFAT signaling by the calcineurin inhibitor cyclosporine A impairs primordial T cell activation, clonal expansion, and infection clearance. Mechanistically, Nile tilapia NFAT interacts with several other transcription factors for potent gene expression, and T cells in this nontetrapod employ Cabin1 and DYRK1A to regulate NFAT nuclear import and export, respectively. To the best of our knowledge, this study is the first to demonstrate the regulatory mechanism of Ca-NFAT signaling on T cell immunity in a nontetrapod species. We suggest that modulation of T cell immunity by Ca-NFAT signaling is a primitive strategy that already existed prior to the divergence of bony fish from the tetrapod lineage. The findings of this study provide valuable perspectives for understanding the evolution of adaptive immune system.
Impact of POR and CYP3A5 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in the Early Post-operative Period Following Kidney Transplantation.
Phupradit Annop,Vadcharavivad Somratai,Ingsathit Atiporn,Kantachuvesiri Surasak,Areepium Nutthada,Sra-Ium Supasil,Auamnoy Titinun,Sukasem Chonlaphat,Sumethkul Vasant,Kitiyakara Chagriya
Therapeutic drug monitoring
BACKGROUND:Tacrolimus, a critical dose drug, is widely used in transplantation. Knowing the contribution of genetic factors, which significantly influence tacrolimus variability, is beneficial in the personalization of its starting dose. The significant impact of CYP3A5*3 polymorphisms on tacrolimus exposure has been reported. Conflicting results of the additional influence of POR*28 polymorphisms on tacrolimus pharmacokinetic interindividual variability have been observed among different populations. The objective of this study was to explore the interaction between POR*28 and CYP3A5*3 polymorphisms and their main effects on tacrolimus trough concentration to dose ratios on day 7 after kidney transplantation. METHODS:Two hundred sixteen adult kidney transplant recipients participated in this retrospective study. All participants received a twice daily tacrolimus regimen. Blood samples and data were collected on day 7 after transplantation. A 2-way analysis of covariance was performed. Tested covariates were age, hemoglobin, serum albumin, and prednisolone dose. RESULTS:A 2 × 2 analysis of covariance revealed that the interaction between CYP3A5 polymorphisms (CYP3A5 expresser and CYP3A5 nonexpresser) and POR polymorphisms (POR*28 carrier and POR*28 noncarrier) was not significant (F(1, 209) = 2.473, P = 0.117, (Equation is included in full-text article.)= 0.012). The predicted main effect of CYP3A5 and POR polymorphisms was significant (F(1, 209) = 105.565, P < 0.001, (Equation is included in full-text article.)= 0.336 and F(1, 209) = 4.007, P = 0.047, (Equation is included in full-text article.)= 0.019, respectively). Hemoglobin, age, and steroid dose influenced log C0/dose of tacrolimus (F(1, 209) = 20.612, P < 0.001, (Equation is included in full-text article.)= 0.090; F(1, 209) = 14.360, P < 0.001, (Equation is included in full-text article.)= 0.064; and F(1, 209) = 5.512, P = 0.020, (Equation is included in full-text article.)= 0.026, respectively). CONCLUSIONS:After adjusting for the influences of hemoglobin, age, and prednisolone dose, significant impacts of the CYP3A5 and POR polymorphisms on tacrolimus exposure were found. The effect of POR*28 and CYP3A5*3 polymorphisms during the very early period after kidney transplantation is independent of each other.
Identification and metabolomic analysis of chemical elicitors for tacrolimus accumulation in Streptomyces tsukubaensis.
Wang Cheng,Huang Di,Liang Shaoxiong
Applied microbiology and biotechnology
Tacrolimus is a widely used immunosuppressive agent in the treatment of various clinical diseases. However, the low fermentation yield seriously limits its further application. To stimulate tacrolimus synthesis, nine chemical elicitors of five groups were evaluated for their effects on tacrolimus accumulation in S. tsukubaensis. The results showed that sodium butyrate (SB), dimethylsulfoxide (DMSO), and LaCl could increase tacrolimus accumulation by more than 30%. Cumulative effects of different chemical elicitors exhibited that the highest tacrolimus yield was improved by 64.7% (303.60 mg/L) in DMSO and La treatment, compared to the control. To decipher possible response mechanism, a weighted correlation network analysis (WGCNA) based on metabolomics was employed and datasets showed 13 distinct metabolic modules and 16 hub metabolites were possibly related to the stimulatory roles of DMSO, La, SB, and their combination treatments. The pathway analysis further exhibited that central carbon metabolism, amino acid metabolism, and fatty acid metabolism showed significant differences in the above chemical elicitor treatments. Thereinto, the carboxylation of propionyl-CoA from isoleucine and methionine degradation was first confirmed to be the main source of methylmalonyl-CoA by RT-PCR analysis in DMSO and La treatment. By further strengthening of the supply of methylmalonyl-CoA precursor in DMSO and La treatment, the final tacrolimus yield could reach to 372.12 mg/L, 2.02-fold higher than the control. To our knowledge, this is the first study to unveil the potential mechanism of different chemical elicitor stresses in S. tsukubaensis based on metabolomics, and the established information provide valuable guidance for further improving tacrolimus production.
Type 2 diabetes and cardiometabolic risk may be associated with increase in DNA methylation of .
Ortiz Robin,Joseph Joshua J,Lee Richard,Wand Gary S,Golden Sherita Hill
Background:Subclinical hypercortisolism and hypothalamic-pituitary-adrenal (HPA) axis dysfunction are associated with type 2 diabetes (T2DM), cardiovascular disease, and metabolic dysfunction. Intronic methylation of has been implicated as a potential indicator of chronic cortisol exposure. Our overall objective in this study was to determine the association of chronic cortisol exposure, measured via percent methylation of at intron 2, with percent glycosylated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-cholesterol), waist circumference (WC), and body mass index (BMI), in a clinic-based sample of 43 individuals with T2DM. Results:Greater percent methylation of the intron 2 at one CpG-dinucleotide region was significantly associated with higher HbA1c ( = 0.535, = 0.003) and LDL cholesterol ( = 0.344, = 0.037) and a second CpG-dinucleotide region was significantly associated with higher BMI and WC ( = 0.516, = 0.001; = 0.403, = 0.006, respectively). Conclusions: methylation may be a marker of higher metabolic risk in T2DM, possibly secondary to higher exposure to cortisol. Further work should aim to assess the longitudinal association of with cardiovascular disease and glycemic outcomes in T2DM as a first step in understanding potential preventive and treatment-related interventions targeting the HPA axis.
FKBP5 expression in human adipose tissue: potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes.
Sidibeh Cherno O,Pereira Maria J,Abalo Xesus M,J Boersma Gretha,Skrtic Stanko,Lundkvist Per,Katsogiannos Petros,Hausch Felix,Castillejo-López Casimiro,Eriksson Jan W
PURPOSE:Here, we explore the involvement of FKBP51 in glucocorticoid-induced insulin resistance (IR) in human subcutaneous adipose tissue (SAT), including its potential role in type 2 diabetes (T2D). Moreover, we assess the metabolic effects of reducing the activity of FKBP51 using the specific inhibitor SAFit1. METHODS:Human SAT was obtained by needle biopsies of the lower abdominal region. FKBP5 gene expression was assessed in fresh SAT explants from a cohort of 20 T2D subjects group-wise matched by gender, age and BMI to 20 non-diabetic subjects. In addition, human SAT was obtained from non-diabetic volunteers (20F/9M). SAT was incubated for 24 h with or without the synthetic glucocorticoid dexamethasone and SAFit1. Incubated SAT was used to measure the glucose uptake rate in isolated adipocytes. RESULTS:FKBP5 gene expression levels in SAT positively correlated with several indices of IR as well as glucose area under the curve during oral glucose tolerance test (r = 0.33, p < 0.05). FKBP5 gene expression levels tended to be higher in T2D subjects compared to non-diabetic subjects (p = 0.088). Moreover, FKBP5 gene expression levels were found to inversely correlate with lipolytic, lipogenic and adipogenic genes. SAFit1 partly prevented the inhibitory effects of dexamethasone on glucose uptake. CONCLUSIONS:FKBP5 gene expression in human SAT tends to be increased in T2D subjects and is related to elevated glucose levels. Moreover, FKBP5 gene expression is inversely associated with the expression of lipolytic, lipogenic and adipogenic genes. SAFit1 can partly prevent glucose uptake impairment by glucocorticoids, suggesting that FKBP51 might be a key factor in glucocorticoid-induced IR.
Comparative Analysis of Calcineurin Inhibitor-Based Methotrexate and Mycophenolate Mofetil-Containing Regimens for Prevention of Graft-versus-Host Disease after Reduced-Intensity Conditioning Allogeneic Transplantation.
Chhabra Saurabh,Liu Ying,Hemmer Michael T,Costa Luciano,Pidala Joseph A,Couriel Daniel R,Alousi Amin M,Majhail Navneet S,Stuart Robert K,Kim Dennis,Ringden Olle,Urbano-Ispizua Alvaro,Saad Ayman,Savani Bipin N,Cooper Brenda,Marks David I,Socie Gerard,Schouten Harry C,Schoemans Helene,Abdel-Azim Hisham,Yared Jean,Cahn Jean-Yves,Wagner John,Antin Joseph H,Verdonck Leo F,Lehmann Leslie,Aljurf Mahmoud D,MacMillan Margaret L,Litzow Mark R,Solh Melhem M,Qayed Muna,Hematti Peiman,Kamble Rammurti T,Vij Ravi,Hayashi Robert J,Gale Robert P,Martino Rodrigo,Seo Sachiko,Hashmi Shahrukh K,Nishihori Taiga,Teshima Takanori,Gergis Usama,Inamoto Yoshihiro,Spellman Stephen R,Arora Mukta,Hamilton Betty K
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
The combination of a calcineurin inhibitor (CNI) such as tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) has been commonly used for graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), but there are limited data comparing efficacy of the 2 regimens. We evaluated 1564 adult patients who underwent RIC alloHCT for acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) from 2000 to 2013 using HLA-identical sibling (matched related donor [MRD]) or unrelated donor (URD) peripheral blood graft and received CYSP or TAC with MTX or MMF for GVHD prophylaxis. Primary outcomes of the study were acute and chronic GVHD and overall survival (OS). The study divided the patient population into 4 cohorts based on regimen: MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP. In the URD group, MMF-CYSP was associated with increased risk of grade II to IV acute GVHD (relative risk [RR], 1.78; P < .001) and grade III to IV acute GVHD (RR, 1.93; P = .006) compared with MTX-TAC. In the URD group, use of MMF-TAC (versus MTX-TAC) lead to higher nonrelapse mortality. (hazard ratio, 1.48; P = .008). In either group, no there was no difference in chronic GVHD, disease-free survival, and OS among the GVHD prophylaxis regimens. For RIC alloHCT using MRD, there are no differences in outcomes based on GVHD prophylaxis. However, with URD RIC alloHCT, MMF-CYSP was inferior to MTX-based regimens for acute GVHD prevention, but all the regimens were equivalent in terms of chronic GVHD and OS. Prospective studies, targeting URD recipients are needed to confirm these results.
FKBP1A rs6041749 polymorphism is associated with allograft function in renal transplant patients.
Wu Zhuo,Xu Qinxia,Qiu Xiaoyan,Xu Luyang,Jiao Zheng,Zhang Ming,Zhong Mingkang
European journal of clinical pharmacology
AIM:To investigate the potential impact of single-nucleotide polymorphisms (SNPs) in the FK506-binding protein (FKBP)-calcineurin (CaN)-nuclear factor of activated T cells (NFAT) signaling pathway on the efficacy and safety of tacrolimus (TAC) in Chinese renal transplant patients. METHODS:Seventy-seven tag SNPs were detected in 146 patients who were on TAC-based maintenance immunosuppression and who followed up for at least 2 years. The relationships of these polymorphisms with clinical outcomes such as acute rejection, acute nephrotoxicity, pneumonia, and estimated glomerular filtration rate (eGFR) were explored. For the FKBP1A rs6041749 polymorphism, which has a significant association with renal function over time, a preliminary functional analysis was performed using a dual-luciferase reporter gene system. RESULTS:The patients with FKBP1A rs6041749 TT genotype had a more stable eGFR level than CC and CT carriers (P = 2.08 × 10) during the 2 years following transplantation. Dual-luciferase reporter assay results showed that the rs6041749 C variant could enhance the relative luciferase activity compared with the T variant, which indicated that the rs6041749 C allele may increase the FKBP1A gene transcription. In addition, we did not find any association between these genetic variants and the risk of acute rejection, acute nephrotoxicity, and pneumonia in renal transplant patients receiving TAC-based immunosuppression. CONCLUSIONS:FKBP1A rs6041749 C allele carriers are at higher risk for eGFR deterioration. The variant might serve as a biomarker to predict allograft function in renal transplant patients.
Influence of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics/Pharmacodynamics of Tacrolimus in Pediatric Patients.
Yang Mengjie,Huan Gui,Wang Mei
Current drug metabolism
BACKGROUND:Single Nucleotide Polymorphisms (SNPs) are very common variants of many genes and are also promising markers associated with drug reactions in pharmacogenomics research. In pediatric organ transplantation, tacrolimus is a major immunosuppressive agent used to prevent organ rejection. The SNP of these genes have been studied extensively in adult population, but there is no systematic review in children. This article focuses on the effects of ABCB1 and CYP3A SNPs on tacrolimus in children who are undergoing organ transplantations. METHODS:We searched the literature that provided the effect of SNP on metabolism and pharmacokinetics of tacrolimus in pediatric patients in Google, Science Direct and PubMed. Then we accessed the methods used in these studies, the sample size, the model and the conclusions they have obtained. RESULTS:We found that there is no evidence shown that CYP3A4 SNP has an influence on the pharmacokinetic/ pharmacodynamics of tacrolimus in the population of children. Moreover, most studies have failed to find a link between the ABCB1 SNP and the pharmacokinetics of tacrolimus in children. However, although the amount of literature is limited, it does show a link between ABCB1 SNPs and tacrolimus pharmacodynamics. In addition, the literature shows a strong link between CYP3A5 SNP and pharmacokinetics of tacrolimus, but there is no direct evidence that CYP3A5 SNP has the same effect on the pharmacodynamics of tacrolimus. CONCLUSION:More standardized clinical trials are needed to assess the relationship between CYP3A5 SNP and tacrolimus pharmacodynamics in children, particularly in terms of acute rejection and nephrotoxicity.
Impact of single nucleotide polymorphisms on P450 oxidoreductase and peroxisome proliferator-activated receptor alpha on tacrolimus pharmacokinetics in renal transplant recipients.
Si Shuhui,Wang Zijie,Yang Haiwei,Han Zhijian,Tao Jun,Chen Hao,Wang Ke,Guo Miao,Tan Ruoyun,Wei Ji-Fu,Gu Min
The pharmacogenomics journal
The P450 oxidoreductase (POR) and peroxisome proliferator-activated receptor alpha (PPARA) genes are associated with the activity of cytochrome P450 enzymes in vivo. We aimed to investigate the impact of single nucleotide polymorphisms (SNPs) in the POR and PPARA genes on the pharmacokinetics of tacrolimus (TAC) in renal transplant recipients. A total of 220 recipients were assessed and 105 recipients were included for final quantitative analysis. Blood samples were collected and DNA was extracted. Targeting sequencing based on next-generation sequencing was applied to detect the SNPs in the POR and PPARA genes. In addition, a systematic review and meta-analysis was performed to comprehensively evaluate the influence of POR and PPARA mutations on the TAC concentrations. A total of 81 SNPs were obtained. Three SNPs (POR*28, Chr7:75619677 and Chr7:75614288) were found to be significantly associated with the TAC pharmacokinetics at 3 months, 6 months, and more than 12 months. No significant association was observed in the combined effect analysis of CYP3A4*1G and CYP3A5*3 with three significant SNPs in the POR gene. Age, post-transplant duration, and the use of sirolimus were identified as the most important factors that influenced the TAC concentrations. A meta-analysis of four studies results and our cohort indicated that compared with recipients carrying the CT or TT genotypes, recipients carrying the CC genotypes of POR*28 showed significantly higher TAC concentrations. Our study suggested the positive influence of mutations in the POR gene on TAC exposure at 3 months after kidney transplantation.
Crocin Ameliorates Atopic Dermatitis Symptoms by down Regulation of Th2 Response via Blocking of NF-κB/STAT6 Signaling Pathways in Mice.
Sung Yoon-Young,Kim Ho Kyoung
Crocin, a major constituent of , is a natural colorant carotenoid compound that has been reported to have anti-inflammatory effects. This study investigated the therapeutic effects of crocin on mice with atopic dermatitis induced by crude extract, which is a common environmental allergen in house dust that causes atopic dermatitis in humans. Crocin application ameliorated crude extract-induced atopic dermatitis symptoms by inhibiting the dermatitis severity score, ear thickness, and serum immunoglobulin E levels in NC/Nga mice. The increases in epidermal thickness and dermal inflammatory cells (eosinophil and mast cells) infiltrations observed on the dorsal back skin of atopic dermatitis control mice were inhibited in a dose-dependent manner by topical application of crocin in atopic dermatitis treatment mice. Crocin inhibited the crude extract-induced increase of thymus and activation-regulated chemokines, interleukin (IL)-4, and IL-13 on the dorsal skin of mice. Crocin also inhibited crude extract-induced activation of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription (STAT) 6. These results show that crocin ameliorates atopic dermatitis symptoms by down regulation of the Th2 cells-mediated immune response via blocking of NF-κB/STAT6 signaling pathways.
Pharmacogenetics of Membrane Transporters of Tacrolimus in Solid Organ Transplantation.
Tron Camille,Lemaitre Florian,Verstuyft Céline,Petitcollin Antoine,Verdier Marie-Clémence,Bellissant Eric
Membrane transporters play an essential role in the pharmacokinetics of drugs as they mediate exchanges between biological compartments. Tacrolimus is characterized by wide interpatient variability in terms of its pharmacokinetics that may in part be due to genetic factors. The pharmacogenetics of drug transporters is therefore a promising area to explore in the clinical pharmacology of tacrolimus. The aim of this review is to provide an overview of currently available data regarding the pharmacogenetics of membrane transporters that may be involved in the interindividual variability of the response to tacrolimus. Several genetic variants in genes coding for influx or efflux membrane transporters (e.g. ABCB1, ABCC2, ABCC8, SLC30A8, SLCO1B1/3, SLC28A1, SLC22A11, and SLC28A3) have been associated with tacrolimus pharmacokinetics variability or the occurrence of toxicity; however, there is still a degree of controversy as to the impact of these variants in vivo and further investigations are needed to confirm these results in larger cohorts and to validate the relevance of such genetic biomarkers for personalization of immunosuppressive therapy in solid organ transplantations. The relationship between transporter polymorphisms and the intracellular concentration of tacrolimus should also be further investigated. Finally, the main challenge could be elucidation of the interplay of biological mechanisms underlying genetic variations that alter the drug concentration or its clinical effect.
Polymorphisms in IMPDH2, UGT2B7, and CES2 genes influence the risk of graft rejection in kidney transplant recipients taking mycophenolate mofetil.
Cilião Heloísa Lizotti,Camargo-Godoy Rossana Batista Oliveira,Souza Marilesia Ferreira de,Zanuto Amanda,Delfino Vinicius Daher Alvares,Cólus Ilce Mara de Syllos
Mutation research. Genetic toxicology and environmental mutagenesis
The immunosuppressant mycophenolic acid (MPA), derived from the prodrug mycophenolate mofetil (MMF), is a drug used widely by kidney transplant recipients. This drug selectively inhibits inosine monophosphate dehydrogenase that controls the proliferation of lymphocytes, aiding in the prevention of rejection of the transplanted organ. Polymorphisms in key genes involved in MMF metabolism may alter the function of the enzymes encoded by them and contribute to interindividual variability in the response to the drug and its efficacy. The aim of this study was to investigate the association of nine polymorphic variants of eight genes involved in MMF pharmacokinetics, with rejection and adverse effects exhibited by kidney transplant recipients who use this drug. Our sample comprised 145 kidney transplant recipients undergoing post-transplant treatment whose immunosuppressive therapy consisted of MMF and corticosteroid combined or not with a calcineurin inhibitor or mTOR inhibitor. The average age of the patients was 46.9 ± 12.5 years, and they underwent transplantation 7 ± 5.71 years ago. The combination of the T/C and C/C genotypes of the polymorphism rs11706052 (IMPDH2) was associated with a 4.2-fold protection, and the combination of the genotypes A/G and G/G of the polymorphism rs7438135 (UGT2B7) showed a 2.4-fold protection, against rejection. The association of T/C and C/C genotypes in the SNP rs11706052 (IMPDH2) with the occurrence of rejection episodes considering only patients who received immunosuppressive drug MMF associated with cyclosporine or tacrolimus and corticoids, demonstrated association with a protection against rejection 15.6-fold. The T/T genotype of the polymorphism rs2241409 (CES2) was associated with a 7.2-fold increased risk of rejection. Therefore, these polymorphisms that showed a strong association with rejection episodes should be considered in future studies on new prognostic markers for rejection in patients treated with MMF.
Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients.
Campos-Salazar Antony Brayan,Genvigir Fabiana Dalla Vecchia,Felipe Claudia Rosso,Tedesco-Silva Helio,Medina-Pestana José,Monteiro Gabriela Vieira,Basso Rodrigo de Gouveia,Cerda Alvaro,Hirata Mario Hiroyuki,Hirata Rosario Dominguez Crespo
Frontiers in pharmacology
Monitoring of immunosuppressive drugs, such as calcineurin and mTOR inhibitors, is essential to avoid undesirable kidney transplant outcomes. Polymorphisms in pharmacokinetics-related genes have been associated with variability in blood levels of immunosuppressive drugs and adverse effects, but influence of pharmacodynamics-related genes remains to be elucidated. The influence of polymorphisms in genes of the mTOR and calcineurin signaling pathways on long-term clinical outcomes was investigated in Brazilian kidney transplant recipients within the 1-year post-transplant. Two-hundred and sixty-nine kidney transplant recipients were enrolled at a kidney transplant center in São Paulo city, Brazil, and treated with tacrolimus plus everolimus or mycophenolate sodium (clinical trial NCT01354301). Clinical and laboratory data, including renal function parameters and drug blood levels were recorded. Genomic DNA was extracted from blood samples. Polymorphisms in rs1057079 (c.4731G>A), rs1135172 (c.1437T>C), and rs1064261 (c.2997C>T); rs3730251 (c.249G>A); rs6033557 (n.259+24936T>C); rs2159370 (c.-2110G>T); and rs3761548 (c.-23+2882A>C) and rs2232365 (c.-22-902A>G) were analyzed by real-time PCR. Frequencies of gene polymorphisms did not differ among the treatment groups. Analysis of primary outcomes showed that patients carrying c.1437CC and c.-23+2882CC genotypes had higher serum creatinine than non-carriers ( < 0.05) at 1-year post-transplant. c.4731G allele (AG+GG genotype) was associated with increased risk for acute rejection (OR = 3.53, 95% CI = 1.09-11.48, = 0.037). Moreover, 1-year cumulative incidence of rejection was higher in c.4731G allele carriers compared to AA genotype carriers ( = 0.027). Individually, analysis of secondary outcomes revealed that c.-2110GG genotype carriers had higher risk of leukopenia, n.259+24936C allele carriers had increased risk of constipation, and c.-22-902A or c.-23+2882A allele had higher risk of gastrointestinal disorders ( < 0.05). However, these results were not maintained in the multivariable analysis after -value adjustment. In conclusion, variants in genes of mTOR and calcineurin pathways are associated with long-term impaired renal function, increased risk of acute rejection, and, individually, with adverse events in Brazilian kidney transplant recipients.
Effect of tacrolimus dispositional genetics on acute rejection in the first 2 weeks and estimated glomerular filtration rate in the first 3 months following kidney transplantation.
Hu Rong,Barratt Daniel T,Coller Janet K,Sallustio Benedetta C,Somogyi Andrew A
Pharmacogenetics and genomics
BACKGROUND:CYP3A4/5 and P-glycoprotein (P-gp, ABCB1) affect tacrolimus (TAC) exposure in T cells and kidney cells. Genetic variability of these genes has been widely studied for effects on acute rejection and kidney function after transplantation, but findings remain contradictory. In addition, cytochrome P450 reductase (POR) is important for CYP3A4/5 activity, and the pregnane X receptor (NR1I2) regulates CYP3A4/5 and P-gp expression. However, the relationship between POR and NR1I2 genetics and acute rejection and kidney function has not been extensively investigated. OBJECTIVE:The aim of this study was to investigate the effect of ABCB1 (61A>G, 1199G>A, 1236C>T, 2677G>T, 3435C>T), CYP3A4*22, CYP3A5*3, NR1I2 (8055C>T, 63396C>T) and POR*28 genotypes/haplotypes on acute rejection and kidney function in the first 3 months after transplant. PARTICIPANTS AND METHODS:The study included 165 kidney transplant recipients, who received TAC, mycophenolate and prednisolone, and 129 donors. TAC dose was adjusted to target trough blood concentrations of 8-15 ng/ml by therapeutic drug monitoring. Recipient and donor genotype/haplotype differences in acute rejection incidence within the first 2 weeks after transplant were assessed by logistic regression, adjusting for induction therapy, human leucocyte antigen mismatches, kidney transplant number, peak panel-reactive antibodies and donor type. Recipient and donor genotype/haplotype differences in estimated glomerular filtration rate in the first 3 months after transplant were assessed by linear mixed effects analysis, adjusting for acute rejection, delayed graft function and donor type. RESULTS:No genetic factors significantly affected acute rejection or estimated glomerular filtration rate after correction for multiple comparisons (P>0.004). CONCLUSION:Recipient and donor dispositional genetics had no significant effect on short-term clinical outcomes in kidney transplant patients receiving TAC therapeutic drug monitoring.
Switching Immunosuppression From Cyclosporine to Tacrolimus in Kidney Transplant Recipients Based on CYP3A5 Genotyping.
Wang Xuebin,Yang Yunyun,Liu Zhengyue,Xiao Chengwu,Gao Lihong,Zhang Wenjing,Zhang Wenwen,Wang Zhuo
Therapeutic drug monitoring
BACKGROUND:Kidney transplant recipients on long-term cyclosporine (CsA) therapy may develop multiple adverse drug events, and immunosuppression conversion from CsA to tacrolimus (Tac) is an option. Genetic variations, especially cytochrome P450 (CYP) 3A5*3, affects Tac dosing. However, little information is available to guide the conversion with regards to patients' pharmacogenomics. We aimed to investigate whether CYP3A5, CYP3A4, and ABCB1 genotyping could contribute to a more precise and individualized initial dosing of Tac at the time of immunosuppressant conversion. METHODS:Genotypes of 5 candidate genes (CYP3A5*3, CYP3A4*1G, ABCB1C1236T, ABCB1C3435T, and ABCB1G2677T/A) were investigated by polymerase chain reaction and restriction fragment-length polymorphism methods in 46 adult kidney transplant recipients requiring immunosuppressant conversion from CsA to TAC. Associations between these functional genetic polymorphisms and the dose-adjusted trough concentrations of CsA and Tac were evaluated, retrospectively. RESULTS:Based on the linear regression analysis, CYP3A5 expressers (*1/*1 and *1/*3) had lower Tac dose-adjusted trough concentrations on days 7, 14, 21, and 28, and they required 1.40- to 1.75-fold higher daily dose to reach the target concentration compared with nonexpressers (*3/*3) on day 28 [0.07 (0.06-0.09) mg/kg/d versus 0.05 (0.02-0.06) mg/kg/d, P = 0.001]. CYP3A4*1G or ABCB1 genetic polymorphisms had no effect on the Tac dose-adjusted trough concentrations. CONCLUSIONS:Our preliminary study supports the use of CYP3A5 genotyping to guide the initial dosing of Tac when converting the immunosuppression therapy from CsA to Tac.
TLR9 rs352139 Genetic Variant Promotes Tacrolimus Elimination in Chinese Liver Transplant Patients During the Early Posttransplantation Period.
Ou Baochi,Liu Yuan,Zhang Tao,Sun Yahuang,Chen Jiayi,Peng Zhihai
BACKGROUND:There are limited markers that could facilitate individualized tacrolimus treatment in the early posttransplantation period. Genetic factors have been found to play critical roles in determining tacrolimus pharmacokinetics. OBJECTIVE:We aimed to examine the association of donor and recipient Toll-like receptor (TLR) polymorphisms with tacrolimus elimination and the potential mechanism for TLR gene polymorphism-mediated tacrolimus metabolism. METHODS:Two independent cohorts including 297 patients receiving liver transplantation (LT) were enrolled in this study (cohort A was composed of 200 patients; cohort B included 97 patients and served as a validation set). Toll-like receptors polymorphisms were genotyped using TaqMan single nucleotide polymorphisms (SNPs) assays. The protein expressions were detected by Western blotting. The metabolism assay was used to quantify tacrolimus elimination. The activity of nuclear factor-kB (NF-kB) was evaluated by luciferase reporter assay. RESULTS:Tacrolimus dose-adjusted trough blood concentrations (C/D) ratios were significantly lower for donor TLR9 rs352139 AG/GG carriers than AA carriers at weeks 1, 2, and 3 after LT. In multivariate analysis, donor and recipient CYP3A5 rs776746 and donor TLR9 rs352139 were independent predictors of tacrolimus C/D ratios in the early period after transplantation in both cohorts. When investigating the combined effects of donor CYP3A5 rs776746 and donor TLR9 rs352139 genotypes, the C/D ratios were remarkably significant at all time points during the first month after LT within the four groups. Furthermore, CYP3A5 mRNA expression in liver tissue was significantly higher for AG/GG patients than AA carriers after LT. In addition, we demonstrated that the TLR9 rs352139 genetic variant promotes tacrolimus metabolism of liver cells via upregulation of CYP3A5, which is dependent on the repression of NF-κB/pregnane X receptor (PXR) signaling. CONCLUSIONS:Donor TLR9 rs352139 genetic variant facilitated tacrolimus elimination during the early stage after LT in Chinese patients, which might be related to the upregulation of CYP3A5 enzyme via the NF-kB/PXR signaling pathway.
Pharmacogenomics research and clinical implementation in Brazil.
Rodrigues-Soares Fernanda,Suarez-Kurtz Guilherme
Basic & clinical pharmacology & toxicology
We searched PubMed entries and the Lattes database of Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a genomewide association study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renal transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Studies verified predisposition of HIV-positive carriers of UGT1A1*28 to severe atazanavir-induced hyperbilirubinaemia, intolerance to 5-fluorouracyl in gastrointestinal cancer patients with deleterious DPYD variants, failure of HCV-infected carriers of IFNL3 rs12979860 to obtain a sustained viral response to PEG-IFN-α, and hypersensitivity reactions to abacavir in HIV-positive carriers of HLA-B*57:01. No prospective analyses of drug therapy outcomes or cost-effectiveness assessments of PGx-guided therapy were found. In conclusion, the limited adoption of PGx-informed drug prescription in Brazil reflects combination of recognized barriers to PGx implementation worldwide plus factors specific to the Brazilian population. The latter include rarity/absence of genetic variants on which international PGx guidelines are based (eg HLA-B*15.02 for phenytoin and carbamazepine) and the caveat of extrapolating to the admixed Brazilian population, guidelines based on categorical variables, such as continental ancestry (eg warfarin guidelines), "race" or ethnicity.
Infectious complications after heart transplantation in patients screened with gene expression profiling.
Moayedi Yasbanoo,Gomez Carlos A,Fan Chun Po S,Miller Robert J H,Bunce Paul E,Tremblay-Gravel Maxime,Foroutan Farid,Manlhiot Cedric,Yee James,Shullo Michael A,Khush Kiran K,Ross Heather J,Montoya Jose G,Teuteberg Jeffrey J
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
BACKGROUND:The risk of infection after heart transplantation is highest within the first year and represents the leading cause of early mortality. In this cohort of patients enrolled in the Outcomes AlloMap Registry (OAR), we sought to describe infection episodes (IEp) resulting in hospitalization, in the early (<1 year) and late (≥1 year) post-transplant period and determine the impact of immunosuppression on incidence of infection. METHODS:The primary aim was to assess the incidence and nature of IEp. The secondary aim was to evaluate the effect of potential risk factors, such as recipient age; sex; body mass index; panel-reactive antibodies; cytomegalovirus (CMV) primary mismatch; prednisone, tacrolimus, and sirolimus levels; and gene expression profile (GEP) score, in the development of IEp. RESULTS:The OAR comprises 1,504 patients, of whom 220 patients (14.6%) had an IEp during a median follow-up period of 382 days (interquartile range [IQR] 230 to 579 days). The cause-specific 5-year hazard ratio for any infection was 2.029 (p = 0.12). The pattern of early infection was consistent with nosocomial and opportunistic causes, whereas later infection was consistent with late-onset opportunistic and community-acquired etiologies. Sixty-two percent of the infections occurred early. In the time-dependent analysis, higher prednisone dose (log prednisone, hazard ratio [HR] 1.30, p = 0.022) was the most significant risk factor for all IEp. CONCLUSIONS:In the OAR cohort, the majority of infections occurred within 1 year after transplantation. Clinicians may consider more aggressive prednisone withdrawal in low-risk patients to reduce IEp.
IL-2 gene polymorphisms affect tacrolimus response in myasthenia gravis.
Shumei Yang,Yi Li,Huanyu Meng,Zhibin Li,Wanlin Jin,Liqun Xu,Huan Yang
European journal of clinical pharmacology
PURPOSE:The IL-2 gene polymorphisms have been reported to be associated with the development of autoimmune disease. However, there are no published studies examining the influence of the IL-2 gene polymorphisms on the response of myasthenia gravis (MG) patients to tacrolimus (Tac). The goal of this study was to investigate the relationship between the polymorphisms of IL-2 and Tac response in MG patients. METHODS:Ninety-two MG patients treated with Tac were studied, including 57 Tac-effective patients and 35 Tac-ineffective patients. Then, we selected four single-nucleotide polymorphisms (SNPs: rs2069776, rs2069772, rs2069762, rs2069763) in the IL-2 gene. Next, we analyzed the distribution of genotypes, allelic frequencies of SNPs, and haplotype frequencies among polymorphisms in the two groups of patients. RESULTS:The distribution of the allelic frequency of the rs2069762 variant differed between the Tac-effective and Tac-ineffective patients (P = 0.02). Genotypes G/T and G/G of rs2069762 were differently distributed between the two groups when the wild genotype T/T was assigned as a reference (P < 0.001 for G/T; P = 0.003 for G/G). Patients with the TAGG haplotype tended to be Tac-ineffective (P < 0.001, OR: 0.15, 95% CI: 0.05-0.43). CONCLUSION:Myasthenia gravis patients with the rs2069762 variant, rs2069762 G/T and G/G genotype, and TAGG haplotype for IL-2 tended to respond poorly to Tac treatment.
Calcineurin inhibitors reduce NFAT-dependent expression of antifungal pentraxin-3 by human monocytes.
Bendíčková Kamila,Tidu Federico,De Zuani Marco,Kohoutková Marcela Hortová,Andrejčinová Ivana,Pompeiano Antonio,Bělášková Silvie,Forte Giancarlo,Zelante Teresa,Frič Jan
Journal of leukocyte biology
Calcineurin (CN) inhibitors are effective clinical immunosuppressants but leave patients vulnerable to potentially fatal fungal infections. This study tested the hypothesis that CN inhibition interferes with antifungal immune defenses mediated by monocytes. We showed that NFAT is expressed by human monocytes, and is activated by exposure to fungal ligands. We confirmed that NFAT translocation potently activated target gene transcription using a human monocytic reporter cell line. Inhibition of CN-NFAT by cyclosporine A significantly reduced monocyte production of TNF-α, IL-10, and MCP-1 proteins in response to pattern recognition receptor ligands as well as to Aspergillus fumigatus conidia. Moreover, we revealed that human monocytes express the antifungal protein pentraxin-3 under control of NFAT. In conclusion, clinical CN inhibitors have the potential to interfere with the novel NFAT-dependent pentraxin-3 pathway as well as antifungal cytokine production in human monocytes, thereby impeding monocyte-mediated defenses against fungal infection in immune-suppressed patients.
FKBP5 rs4713916: A Potential Genetic Predictor of Interindividual Different Response to Inhaled Corticosteroids in Patients with Chronic Obstructive Pulmonary Disease in a Real-Life Setting.
Russo Patrizia,Tomino Carlo,Santoro Alessia,Prinzi Giulia,Proietti Stefania,Kisialiou Aliaksei,Cardaci Vittorio,Fini Massimo,Magnani Mauro,Collacchi Francesco,Provinciali Mauro,Giacconi Robertina,Bonassi Stefano,Malavolta Marco
International journal of molecular sciences
: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and manageable lung disease characterized by large heterogeneity in disease presentation and grades impairment. Inhaled corticosteroids (ICS) are commonly used to manage COPD/COPD-exacerbation. The patient's response is characterized by interindividual variability without disease progression/survival modification. : We hypothesize that a therapeutic intervention may be more effective if single nucleotide polymorphisms (SNPs) are investigated. : In 71 COPD patients under pulmonary rehabilitation, a small number of powerful SNPs, selected according to current literature, were analyzed; namely the glucocorticoid receptor gene NR3C1 (rs6190/rs6189/rs41423247), the glucocorticoid-induced transcript 1 gene (GLCCI1 rs37972), and the related co-chaperone FKBP5 gene (rs4713916). MDR1 rs2032582 was also evaluated. Lung function outcomes were assessed. : A significant association with functional outcomes, namely FEV (forced expiration volume/one second) and 6MWD (six-minutes walking distance), was found for rs4713916 and weakly for rs37972. The genotype rs4713916(GA) and, in a lesser extent, the genotype rs37972(TT), were more favorable than the wild-type. : Our study supports a possible picture of pharmacogenomic control for COPD intervention. rs4713916 and, possibly, rs37972 may be useful predictors of clinical outcome. These results may help to tailor an optimal dose for individual COPD patients based on their genetic makeup.
Population Pharmacokinetics of Mycophenolic Acid Co-Administered with Tacrolimus in Corticosteroid-Free Adult Kidney Transplant Patients.
Rong Yan,Mayo Patrick,Ensom Mary H H,Kiang Tony K L
BACKGROUND AND OBJECTIVE:Mycophenolic acid is commonly prescribed to adult kidney transplant recipients. Mycophenolic acid is extensively metabolized to mycophenolic acid-glucuronide (major metabolite) and mycophenolic acid-acyl-glucuronide (minor metabolite). We hypothesized that (1) adult kidney transplant patients on corticosteroid-free regimens exhibit unique mycophenolic acid population pharmacokinetics compared with patients receiving corticosteroid-based therapy, and (2) mycophenolic acid clearance is directly dependent on glucuronide metabolite formation. METHODS:Non-linear mixed-effects modeling was conducted with MonolixSuite-2018R1 (n = 27). Optimal pharmacokinetic models were selected based on objective function values, standard errors, and biological plausibility. RESULTS:Clinical demographic data were sex (female, 16), age (47 ± 13 years, mean ± standard deviation), weight (70 ± 16 kg), height (165 ± 9 cm), albumin (43 ± 4 g/L), serum creatinine (102 ± 27 µmol/L), estimated glomerular filtration rate (61 ± 16 mL/min/1.73 m), mycophenolic acid dosage (1.4 ± 0.5 g/day, as mycophenolate mofetil), and tacrolimus dosage (5 ± 3 mg/day, immediate release). The population pharmacokinetics of mycophenolic acid can be described by a two-compartment first-order absorption with lag time, and a linear elimination structural model. The apparent oral clearance estimate in the final model (population mean, relative standard error) was 2.87 L/h, 42.3%, which is lower than that reported for similar patients on corticosteroid-based regimens (11.9-26.3 L/h). Other pharmacokinetic parameters were comparable to historical data obtained in corticosteroid-based patients. Both mycophenolic acid-acyl-glucuronide trough concentration and the area under the concentration-time curve ratio were significant covariates that reduced mycophenolic acid apparent oral clearance from 16.5 (base model) to 2.87 L/h. The model was evaluated based on bootstrapping, visual predictive checks, and diagnostic plots. CONCLUSIONS:Our novel findings suggest the potential need to reduce mycophenolic acid dosage in subjects on corticosteroid-free regimens. Corticosteroid-free subjects may also be more sensitive to drug/gene interactions.
Therapeutic concentration achievement and allograft survival comparing usage of conventional tacrolimus doses and CYP3A5 genotype-guided doses in renal transplantation patients.
Anutrakulchai Sirirat,Pongskul Cholatip,Kritmetapak Kittrawee,Limwattananon Chulaporn,Vannaprasaht Suda
British journal of clinical pharmacology
AIMS:Although cytochromeP450(CYP)3A5 gene polymorphism affects personalized tacrolimus doses, there is no consensus as to whether CYP3A5 genotypes should be determined to adjust the doses. The aims were to compare the therapeutic ranges and clinical outcomes between the conventional and genotype-guided tacrolimus doses. METHODS:This randomized controlled study compared 63 cases of the conventional tacrolimus dose group (0.1 mg/kg/day) with 62 cases of the genotype-guided doses group of 0.125, 0.1 and 0.08 mg/kg for CYP3A5*1/*1, *1/*3, and *3/*3 genotypes for the initial 3 days of kidney transplantation. After day 3, dose adjustment occurred in both groups to achieve therapeutic concentrations. RESULTS:The genotype-guided group had an increased proportion of patients with tacrolimus concentrations in the therapeutic range at the steady state on day 3 (40.3 vs 23.8%, P = .048). A lower proportion of over-therapeutic concentration patients was noted in the genotype-guided group in the CYP3A5*3/*3 genotype (9.7 vs 27%, P = .013). Unexpectedly, more delayed graft functions (DGFs) were in the genotype-guided group (41.9 vs 22.2%, P = .018) especially in the CYP3A5*1/*1 participants who might have had an aggravated DGF by a longer ischaemic time and higher serum donor creatinine levels than in the control group. There were no significant differences of glomerular filtration rates or graft or patient survivals over a median 37-month follow-up period. CONCLUSIONS:Determination of the CYP3A5 genotype improved therapeutic range achievement. CYP3A5*1/*1 patients who have high risks of DGF should be closely monitored because of an increased risk of DGF and reduced glomerular filtration rate with high tacrolimus doses.
Impact of , and Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplantation.
Suetsugu Kimitaka,Mori Yasuo,Yamamoto Nanae,Shigematsu Tomohiro,Miyamoto Toshihiro,Egashira Nobuaki,Akashi Koichi,Masuda Satohiro
International journal of molecular sciences
Single nucleotide polymorphisms in drug-metabolizing genes may affect tacrolimus pharmacokinetics. Here, we investigated the influence of genotypes of , , and on the concentration/dose (C/D) ratio of tacrolimus and episodes of acute graft-versus-host disease (GVHD) in Japanese recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty-six patients receiving the first HSCT using tacrolimus-based GVHD prophylaxis were enrolled with written informed consent. During continuous intravenous infusion, HSCT recipients carrying the allele, particularly those with at least one allele, had a significantly lower tacrolimus C/D ratio throughout all three post-HSCT weeks compared to that in recipients with ( < 0.05). The genotype and the concomitant use of voriconazole were independent predictors of an increased tacrolimus C/D ratio during the switch from continuous intravenous infusion to oral administration ( < 0.05). In recipients receiving concomitant administration of voriconazole, our results suggest an impact of not only and genotypes, but also plasma voriconazole concentration. Although switching from intravenous to oral administration at a ratio of 1:5 was seemingly appropriate in recipients with , a lower conversion ratio (1:2-3) was appropriate in recipients with . Our results suggest that , , and polymorphisms are useful biomarkers for individualized dosage adjustment of tacrolimus in HSCT recipients.
The impact of liver transplant recipient and donor genetic variability on tacrolimus exposure and transplant outcome.
Coller Janet K,Ramachandran Jeyamani,John Libby,Tuke Jonathan,Wigg Alan,Doogue Matthew
British journal of clinical pharmacology
This study investigated the effect of recipient and donor genetic variability on dose-adjusted steady-state tacrolimus concentrations (C ) and clinical outcomes 3 and 6 months after liver transplant. Twenty-nine recipients and matched donor blood samples were genotyped for 27 single nucleotide polymorphisms including CYP3A5*3 (rs776746), ABCB1 haplotype and immune genes. Associations between genetic variability and clinical parameters and C and the occurrence of rejection and nephrotoxicity were analysed by multivariate and multinomial logistic regression modelling and Jonckheere-Terpstra tests examined the impact of combined donor/recipient CYP3A5 expression on C . At 3 months post-transplant modelling revealed an association between tacrolimus C and recipient CASP1 rs580523 genotype (P = 0.005), accounting for 52% C variance. Jonckheere-Terpstra tests revealed that as combined donor/recipient CYP3A5 expression increased, C decreased (P = 0.010 [3 months], 0.018 [6 months]). As this is the first report of CASP1 genetic variability influencing tacrolimus C , further validation in larger cohorts is required.
Comparative transcriptome analysis of peripheral blood mononuclear cells in renal transplant recipients in everolimus- and tacrolimus-based immunosuppressive therapy.
Granata Simona,Santoro Gloria,Signorini Lorenzo,Malerba Giovanni,Patuzzo Cristina,Gambaro Giovanni,Stallone Giovanni,Zaza Gianluigi
European journal of pharmacology
To better define the biological impact of immunosuppression on peripheral blood mononuclear cells (PBMC), we employed RNASeq analysis to compare the whole transcriptomic profile of a group of renal transplant recipients undergoing maintenance treatment with Everolimus (EVE) with those treated with Tacrolimus (TAC). Then, obtained results were validated by classical biomolecular methodologies. The statistical analysis allowed the identification of four genes discriminating the 2 study groups: Sushi Domain Containing 4 (SUSD4, P = 0.02), T Cell Leukemia/Lymphoma 1A (TCL1A, P = 0.02), adhesion G protein-coupled receptor E3 (ADGRE3, P = 0.01), Immunoglobulin Heavy Constant Gamma 3 (IGHG3, P = 0.03). All of them were significantly down-regulated in patients treated with EVE compared to TAC. The Area under Receiver Operating Characteristic (AUROC) of the final model based on these 4 genes was 73.1% demonstrating its good discriminative power. RT-PCR and ELISA validated transcriptomic results. Additionally, an in vitro model confirmed that EVE significantly down-regulates (P<0.001) TCL1A, SUSD4, ADGRE3 and IgHG3 in PBMCs as well as in T cells and monocytes isolated from healthy subjects. Taken together, our data, revealed, for the first time, a new four gene-based transcriptomic fingerprint down-regulated by EVE in PBMCs of renal transplant patients that could improve the available knowledge regarding some of the biological/cellular effects of the mTOR-Is (including their antineoplastic and immune-regulatory properties).
Gene-Based Dose Optimization in Children.
Ramsey Laura B,Brown Jacob T,Vear Susan I,Bishop Jeffrey R,Van Driest Sara L
Annual review of pharmacology and toxicology
Pharmacogenetics is a key component of precision medicine. Genetic variation in drug metabolism enzymes can lead to variable exposure to drugs and metabolites, potentially leading to inefficacy and drug toxicity. Although the evidence for pharmacogenetic associations in children is not as extensive as for adults, there are several drugs across diverse therapeutic areas with robust pediatric data indicating important, and relatively common, drug-gene interactions. Guidelines to assist gene-based dose optimization are available for codeine, thiopurine drugs, selective serotonin reuptake inhibitors, atomoxetine, tacrolimus, and voriconazole. For each of these drugs, there is an opportunity to clinically implement precision medicine approaches with children for whom genetic test results are known or are obtained at the time of prescribing. For many more drugs that are commonly used in pediatric patients, additional investigation is needed to determine the genetic factors influencing appropriate dose.
Pharmacogenomics analysis in Chinese pediatric liver transplantation patients with renal toxicity induced by tacrolimus.
Wang Dongdong,Chen Xiao,Fu Meng,Xu Hong,Li Zhiping
Xenobiotica; the fate of foreign compounds in biological systems
Survival for pediatric liver transplantation patients is limited by nephrotoxicity of calcineurin inhibitors tacrolimus. The present study was to explore the association of genetic factors with nephrotoxicity of pediatric liver transplantation patients treated with tacrolimus.Chinese pediatric liver transplantation patients under tacrolimus therapy between March 2014 and August 2018 from Children's Hospital of Fudan University were retrospectively analyzed. A total of 15 patients, including 6 patients with nephrotoxicity induced by tacrolimus and 9 patients without nephrotoxicity, were detected by pharmacogenomics (PGxOne®160). Demographic characteristics and laboratory testing were collected from medical logs. Tacrolimus blood concentrations were extracted from therapeutic drug monitoring (TDM) documents.The risk of renal toxicity induced by tacrolimus in Chinese pediatric liver transplantation patients were positively associated with T allele of cytochrome P450 1A2 () rs2470890 (RR = 2.857, 95% confidence interval = [1.392-5.863]), A allele of dopamine D2 () rs1076560 (RR = 4.375, 95% confidence interval = [1.148-16.676]), T allele of paraoxonase-1 () rs662 (RR = 2.800, 95% confidence interval= [1.184-6.622]), respectively.Pharmacogenomics analysis in Chinese pediatric liver transplantation patients with renal toxicity induced by tacrolimus was firstly reported. The SNPs in 3 genes (, , and ) were associated with risk of tacrolimus-induced nephrotoxicity.
Altered expression of glucose metabolism associated genes in a tacrolimus‑induced post‑transplantation diabetes mellitus in rat model.
Zhang Ling,He Yunqiang,Wu Cunzao,Wu Minmin,Chen Xuehai,Luo Jiao,Cai Yong,Xia Peng,Chen Bicheng
International journal of molecular medicine
Post‑transplantation diabetes mellitus (PTDM) is a known side effect in transplant recipients administered with immunosuppressant drugs, such as tacrolimus (Tac). Although injury of islet cells is considered a major reason for Tac‑induced PTDM, the involvement of insulin resistance in PTDM remains unknown. In the present study, expression levels of adipocytokines, glucose metabolism associated genes and peroxisome proliferator‑activated receptor (PPAR)‑γ in adipose, muscular and liver tissues from a rat model induced with Tac (1 mg/kg/day) were examined. Rats developed hyperglycemia and glucose intolerance after 10 days of Tac administration. A subgroup of diabetic rats was further treated with rosiglitazone (4 mg/kg), a PPAR‑γ activator. Adipose, muscle and liver tissues were obtained on day 15 after induction and the results demonstrated that expression levels of adipocytokines, PPAR‑γ and proteins in the insulin associated signaling pathway varied in the different groups. Rosiglitazone administration significantly improved hyperglycemia, glucose intolerance and expression levels of proteins associated with insulin signaling, as well as adipocytokines expression. The results of this study demonstrated that adipocytokines and PPAR‑γ signaling may serve important roles in the pathogenesis of Tac‑induced PTDM, which may provide a promising application in the treatment of PTDM in the future.
Evaluation of Angiotensinogen M235T and T174M Polymorphisms, Demographic and Clinical Factors in New-Onset Diabetes after Liver Transplantation in Iranian Patients.
Mottaghi S,Azarpira N,Dehshahri A,Khalvati B,Namazi S
International journal of organ transplantation medicine
Background:New-onset diabetes after transplantation (NODAT) is a serious complication which runs the risk of infections, morbidity and mortality. Objective:To evaluate M235T and T174M polymorphisms of angiotensinogen gene along with some demographic and clinical factors including age; sex; body mass index (BMI); model for end-stage liver disease (MELD) score; prednisolone, mycophenolate mofetil and tacrolimus dose; and serum level in NODAT among liver recipients. Methods:In this study 115 patients (53 with and 62 without NODAT) who had no history of diabetes before the transplantation were investigated. Furthermore, 80 randomly selected apparently healthy people (no transplantation) were used as the control group. Two angiotensinogen polymorphisms (M235T and T174M) were studied using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Results:Patients included 68 (59.1%) females and 47 (40.9%) males; they had a mean±SD age of 37.4±16.9 years. The M allele frequency was 55.7% (n=128) in M235T and 20.0% (n=46) in T174M polymorphisms. Binary logistic regression analysis confirmed that age (p=0.005), prednisolone dose (p<0.001) and mutated M235T polymorphism (p=0.003) were independent risk factors. Conclusion:Presence of M235T T allele may significantly (p<0.001) increase the NODAT risk, and increase the likelihood of developing end-stage liver disease (p=0.003). T174M T allele had a significantly (p=0.007) higher frequency in NODAT group.
Multicenter Prospective Study of the Efficacy and Safety of Combined Immunosuppressive Therapy With High-Dose Glucocorticoid, Tacrolimus, and Cyclophosphamide in Interstitial Lung Diseases Accompanied by Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis.
Tsuji Hideaki,Nakashima Ran,Hosono Yuji,Imura Yoshitaka,Yagita Masato,Yoshifuji Hajime,Hirata Shintaro,Nojima Takaki,Sugiyama Eiji,Hatta Kazuhiro,Taguchi Yoshio,Katayama Masaki,Tanizawa Kiminobu,Handa Tomohiro,Uozumi Ryuji,Akizuki Shuji,Murakami Kosaku,Hashimoto Motomu,Tanaka Masao,Ohmura Koichiro,Mimori Tsuneyo
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:Interstitial lung disease (ILD) accompanied by anti-melanoma differentiation-associated gene 5 (anti-MDA-5)-positive dermatomyositis (DM) is often rapidly progressive and associated with poor prognosis. Because there is no established treatment, we undertook this study to prospectively evaluate the efficacy and safety of a combined immunosuppressive regimen for anti-MDA-5-positive DM patients with ILD. METHODS:Adult Japanese patients with new-onset anti-MDA-5-positive DM with ILD (n = 29) were enrolled at multiple study centers from 2014 to 2017. They were treated with a regimen of high-dose glucocorticoids (GCs), tacrolimus, and intravenous cyclophosphamide (IV CYC). Plasmapheresis was used if a patient's condition worsened after the regimen started. The primary end point was 6-month survival, which was compared between this group of patients and a historical control group (n = 15) consisting of anti-MDA-5-positive DM patients with ILD who received step-up treatment (high-dose GC and stepwise addition of immunosuppressant). Secondary end points were 12-month survival rate, adverse events, and changes in laboratory data. RESULTS:The combined immunosuppressive regimen group showed significantly higher 6-month survival rates than the step-up treatment group (89% versus 33%; P < 0.0001). Over a period of 52 weeks, improvements in anti-MDA-5 titers, serum ferritin levels, vital capacity, and chest high-resolution computed tomography scores were observed. The combined immunosuppressive regimen group received IV CYC nearly 20 days earlier with shorter intervals and tended to receive plasmapheresis more often than patients undergoing step-up treatment. Cytomegalovirus reactivation was frequently observed over 52 weeks. CONCLUSION:A combined immunosuppressive regimen is effective for anti-MDA-5-positive DM patients with ILD. Plasmapheresis can be used for additional effect in intractable disease. Patients should be carefully monitored for opportunistic infections during treatment.
Tacrolimus increases the expression level of the chemokine receptor CXCR2 to promote renal fibrosis progression.
Wang Dongdong,Chen Xiao,Fu Meng,Xu Hong,Li Zhiping
International journal of molecular medicine
Tacrolimus is one of the most used and effective immunosuppressive agents currently available in the clinic; however, its use is limited by nephrotoxicity, which is the main secondary effect of this drug. The mechanisms underlying tacrolimus‑induced nephrotoxicity remain unknown. The present study aimed to investigate the mechanism underlying tacrolimus‑induced nephrotoxicity and to identify novel potential targets. Masson staining, Sirius red staining and periodic acid‑silver methenamine staining were used to observe kidney pathological changes. Immunohistochemical and immunofluorescent analyses were performed to examine the expression levels of vimentin, E‑cadherin and α‑smooth muscle actin (α‑SMA). Transcriptomics and bioinformatics analyses were performed to investigate the nephrotoxicity mechanism induced by tacrolimus using RNA‑sequencing, differentially expressed genes identification and annotation, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The present results demonstrated that compared with the normal control group, the tacrolimus nephrotoxicity group exhibited severe renal fibrosis (P<0.05), upregulated vimentin (P<0.01), downregulated E‑cadherin (P<0.05) and upregulated α‑SMA (P<0.01). Transcriptomics and bioinformatics analyses identified the pathway 'cytokine‑cytokine receptor interaction' as the most significantly enriched (P<0.05). Moreover, KEGG pathway enrichment analysis identified that tacrolimus increased the expression levels of chemokine (C‑X‑C) motif ligand (CXCL)1, CXCL2 and CXCL3 and the chemokine receptor C‑X‑C chemokine receptor type 2 (CXCR2). Collectively, the present study suggested that tacrolimus increases the level of chemokine receptor CXCR2 to promote renal fibrosis progression, which is one of the potential mechanisms underlying tacrolimus‑induced nephrotoxicity.
The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: From bench to bedside.
Ling Qi,Huang Haitao,Han Yuqiu,Zhang Chenzhi,Zhang Xueyou,Chen Kangchen,Wu Li,Tang Ruiqi,Zheng Zhipeng,Zheng Shusen,Li Lanjuan,Wang Baohong
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Tacrolimus (TAC), the mainstay of maintenance immunosuppressive agents, plays a crucial role in new-onset diabetes after transplant (NODAT). Previous studies investigating the diabetogenic effects of TAC have focused on the β cells of islets. In this study, we found that TAC contributed to NODAT through directly affecting hepatic metabolic homeostasis. In mice, TAC-induced hypoglycemia rather than hyperglycemia during starvation via suppressing gluconeogenetic genes, suggesting the limitation of fasting blood glucose in the diagnosis of NODAT. In addition, TAC caused hepatic insulin resistance and triglyceride accumulation through insulin receptor substrate (IRS)2/AKT and sterol regulatory element binding protein (SREBP1) signaling, respectively. Furthermore, we found a pivotal role of CREB-regulated transcription coactivator 2 (CRTC2) in TAC-induced metabolic disorders. The restoration of hepatic CRTC2 alleviated the metabolic disorders through its downstream molecules (eg, PCK1, IRS2, and SREBP1). Consistent with the findings from bench, low CRTC2 expression in graft hepatocytes was an independent risk factor for NODAT (odds ratio = 2.692, P = .023, n = 135). Integrating grafts' CRTC2 score into the clinical model could significantly increase the predictive capacity (areas under the receiver operating characteristic curve: 0.71 vs 0.79, P = .048). Taken together, in addition to its impact on pancreatic cells, TAC induces "hematogenous diabetes" via CRTC2 signaling. Liver-targeted management may be of help to prevent or heal TAC-associated diabetes.
Effect of CYP3A5 and ABCB1 Gene Polymorphisms on Tacrolimus Blood Concentration in Renal Transplant Recipients.
Yildirim Engin,Şahin Garip,Kaltuş Zuhal,Çolak Ertugrul
BACKGROUND:Tacrolimus (Tac) is a calcineurin inhibitor (CNI). Its therapeutic range is narrow and pharmacokinetic properties vary among patients. CYP3A5 and MDR1 single-nucleotide polymorphisms (SNPs) are the most effective polymorphisms that play an significant role in the pharmacokinetics of Tac. METHODS:We investigated the influence of CYP3A5 (A6986G) and MDR1 (C3435T) gene polymorphisms on Tac trough concentration (C0), dose requirements (mg/kg), and dose-adjusted concentrations (ng/mL per mg/kg/d). CYP3A5 [*1/*1 (expresser), *1/*3 (expresser); *3/*3 (non-expresser)] and MDR1 (CC, CT, TT) gene polymorphisms were determined by allele-specific polymerase chain reaction in 67 adult Turkish renal transplant patients. The Tac dose (mg/kg/d) and C0 of each patient was acquired from the patient's file and dose-adjusted concentrations (ng/mL per mg/kg/d) were calculated at the 1st, 3rd, 6th, and 12th months after transplantation. The correlated serum hematocrit, platelet, urea, creatinine, and albumin were also determined. RESULTS:The CYP3A5*1/*3 and CYP3A5*3/*3 allelic frequencies were 5.97% and 94.03%, respectively. There were no patients with the CYP3A5*1/*1 genotype. Tac dose was significantly lower in *3/*3 genotype than in *1/*1 genotype (3rd and 6th months: p ≤ 0.001; 12th month: p ≤ 0.05). Dose-adjusted Tac concentration was statistically higher in the *3/*3 genotype than in *1/*1 genotype at the 3rd and 6th months (p ≤ 0.05). The allelic frequencies of MDR1 CC, CT, and TT were 26.87%, 49.25%, and 23.88%, respectively. No statistically significant differences were detected between MDR1 genotypes and in all analyzed laboratory parameters. CONCLUSIONS:CYP3A5 but not MDR1 genetic polymorphisms affected the Tac pharmacokinetics and dose requirements in renal transplant recipients. Pharmacogenetic methods can be used for selecting the initial dose to individualize immunosuppressive therapy.
Clinically significant drug-drug interaction between tacrolimus and fluconazole in stable renal transplant recipient and literature review.
He Jiake,Yu Yang,Yin Chenglong,Liu Hailang,Zou Hua,Ma Jingsheng,Yang Wentao,Liu Ye,Zhong Lin,Chen Xijing
Journal of clinical pharmacy and therapeutics
WHAT IS KNOWN AND OBJECTIVE:Clinical use of fluconazole against fungal infections in renal transplant patients is complicated by the potentially marked and unpredictable drug-drug interactions (DDIs). We report a case of tacrolimus-fluconazole DDI in a stable renal transplant recipient and describe the mechanism, magnitude and duration of this DDI through a literature review. CASE SUMMARY:A 38-year-old woman experienced a 9.1-fold increase in dose-normalized tacrolimus trough level (trough concentration/weight-normalized daily dose) and an 87% decrease in weight-normalized daily dose (daily dose/body weight) in the treatment of documented Candida albicans oesophagitis by fluconazole. After discontinuation of fluconazole for 161 day, a 26% reduction in weight-normalized daily dose was required to maintain therapeutic exposure. WHAT IS NEW AND CONCLUSION:Oral fluconazole has a more significant impact on its drug interactions with tacrolimus than intravenous fluconazole. Gene screening for CYP3A5 6986 A>G and ABCB1 3435 C>T in organ transplant recipients may help in preventing DDI and facilitating tacrolimus dose adjustment.
Clinical observation on the effect of Wuzhi soft capsule on FK506 concentration in membranous nephropathy patients.
Zhang Zhu,Lu Xiaobei,Dong Leipeng,Ma Jiwei,Fan Xiaoguang
The current research aimed to investigate the correlation between the effect of Wuzhi soft capsule (WZC) on FK506 concentration and CYP3A5 gene polymorphism in patients with membranous nephropathy (MN).Seventy-five patients with idiopathic MN were enrolled and divided according to the expression of CYP3A5 gene metabolic enzyme into group A (CP3A5 metabolic enzyme function expression types CYP3A5*1/*1 type and CYP3A5*1/*3 type), and group B (non-expression type CYP3A5*3/*3 type). All patients were given oral administration of tacrolimus capsule at the initial dose of 1 mg for twice a day 1 hour before breakfast and dinner. Afterwards, the oral administration of WZC was added at the dose of 0.5 g for 3 times a day within half an hour after 3 meals.The blood concentrations of FK506 in groups A and B were significantly higher than those before administration. Compared with that before administration, the FK506 blood concentration was increased by 3.051 ± 0.774 ng/ml after adding the WZC. Besides, the blood concentrations of FK506 in group A were lower than those in group B before and after administration; meanwhile, the 24 hours total urine protein and the biochemical indexes in both groups displayed no statistically significant difference. Only 1 case of diarrhea was observed, which was relieved after the reduction of tacrolimus.Wuzhi soft capsule can significantly increase the blood concentration of FK506 in MN patients. Moreover, the CYP3A5 genotyping should be considered when WZC is used to increase the blood concentration of FK506.
Nuclear factor of activated T cells as potential pharmacodynamic biomarker for the risk of acute and subclinical rejection in de novo liver recipients.
Millán Olga,Ruiz Pablo,Fortuna Virginia,Navasa Miquel,Brunet Mercè
Liver international : official journal of the International Association for the Study of the Liver
BACKGROUND & AIMS:Nuclear factor of activated T cell-regulated gene expression (NFAT-RGE) has been proposed as a pharmacodynamic biomarker for tacrolimus (Tac) and cyclosporine (CsA). Our aim was to evaluate the role of NFAT-RGE in modulating intralymphocytary IL-2 and IFN-γ expression and its clinical utility as an early non-invasive predictive biomarker for the risk of acute rejection (AR) and infection in de novo liver transplant (LT) recipients. METHODS:Fifty-six LT recipients treated with Tac or CsA [with and without mycophenolate mofetil (MMF)] were included: 30 free of rejection or infection, 11 rejectors (T cell-mediated acute rejection), 5 with subclinical rejection (SCR) and 10 with cytomegalovirus (CMV) infection. Within the first 3 months after transplantation, NFAT-RGE of IL-2, IFN-γ and GM-CSF and intralymphocytary synthesis of IL-2 and IFN-γ were evaluated by real-time PCR and flow cytometry respectively. RESULTS:A significant increase in NFAT-RGE was observed in patients who experienced TCMAR (75% [42-100%]) or SCR (41% [18-78%]) compared with patients without rejection or infection (14% [2-23%]). Positive correlations between the %NFAT-RGE-IFN and both the %CD8CD69IFN-γ and %CD4CD69IFN-γ and between the %NFAT-RGE-IL2 and the %CD8CD69IL2 were observed. NFAT-RGE was significantly lower in CMV patients than in non-infected patients. Finally, an inverse correlation between the Tac or CsA concentration and inhibition of NFAT-RGE were observed. CONCLUSIONS:Sequential post-transplantation NFAT-RGE monitoring combined with intralymphocytary IL-2 and IFN-γ before transplantation and at the first and third month post-transplantation may be key predictive and diagnostic biomarkers for the risk of TCMAR and SCR and better guide CNi therapy in LT patients.
Melding Pharmacogenomic Effect of and CYP3A5 Gene Polymorphism on Tacrolimus Dosing in Renal Transplant Recipients in Northern India.
Prasad Narayan,Jaiswal Akhilesh,Behera Manas Ranjan,Agarwal Vikas,Kushwaha Ravi,Bhadauria Dharmendra,Kaul Anupama,Gupta Amit
Kidney international reports
Introduction:Tacrolimus (TAC) is the mainstay immunosuppressant for renal transplantation. A narrow therapeutic index, multiple drug interactions, and interindividual variability in pharmacokinetics make it obligatory to monitor therapeutic drug levels. The () and CYP3A5 gene polymorphism may blend to achieve the optimal level. The optimal dose as per body weight is difficult to single out in the early posttransplantation period. In this study, we aimed to analyze the melding effect of both gene polymorphisms and to elicit the dose depending on the combination of genetic single nucleotide polymorphisms (SNPs) in northern Indian transplant recipients, for whom data are limited. Methods:The daily TAC dose, weight-adjusted doses (mg/kg per day), TAC trough blood concentration (average of at least 3 levels), dose normalized with a corresponding dose using TAC concentration/weight-adjusted dose ratio (ng/ml per mg/kg per day) of 248 patients were recorded. All recipients were genotyped for the SNPs of CYP3A5 at intron 3 A6986G (the *3 or *1 allele), at exons 12 (C1236T), 21 (G2677A/T), and 26 (C3435T). We analyzed the blending effect of mutant SNPs of the gene and CYP3A5 for optimized TAC levels. Results:Among CYP3A5 genotypic variants, the dose-adjusted TAC level was significantly lower, and the TAC dose required to achieve the target level was significantly higher, in CYP3A5*1*1 (expressor) than that of CYP3A5*1*3 and CYP3A5*3*3. Of the gene SNPs, only the G2677T/A homozygous mutant was significantly associated with TAC level, and it was strongly correlated with P-gp expression.The daily TAC dose requirement was highest with a combination of CYP3A5*1*1 and homozygous mutant TT+AA genotype of G2677T/A, and was lowest with CYP3A5*3*3 and wild-type GG of the G2677T/A genotype. Conclusion:Both CYP gene and gene polymorphism affect TAC dose requirements, and there is a need to look for both in an individual to achieve the target trough concentration.
Donor and recipient P450 gene polymorphisms influence individual pharmacological effects of tacrolimus in Chinese liver transplantation patients.
Liu Jianyu,Ouyang Yabo,Chen Dexi,Yao Bo,Lin Dongdong,Li Zhiqiang,Zang Yunjin,Liu Huan,Fu Xiaoyue
The immunosuppressant drug tacrolimus (Tac) used for the prevention of immunological rejection is a metabolic substrate of cytochrome P450 enzymes. This study was designed to evaluate the short-term and long-term potential influence of single-nucleotide polymorphisms (SNPs) in CYP450 genes of liver transplant (LT) recipients as well as the donors on individual pharmacological effects of Tac and to guide individualized-medication from the perspective of pharmacogenomics. Twenty-one SNPs of the CYP450 gene were genotyped for both recipients and donors in 373 LT patients receiving Tac-based immunosuppressants. The Tac concentration/dosage ratio (C/D) was evaluated from the initial medication until one year after LT. The C/D ratio was significantly higher when the donor and/or recipient genotype of CYP3A5 rs776746 was G/G or rs15524 was T/T or rs4646450 was C/C all through one year after transplantation. Comparing the effect of donor gene variants of rs776746, rs15524, and rs4646450 on Tac C/D ratios with the recipients, statistically significant differences were found between the donor T/T group and the recipient T/T group in rs15524 at 1 month and 6 months, and at 6 months, the donor C/C group differed from the recipient C/C group in rs4646450. In conclusion, rs776746, rs15524, and rs4646450 of CYP3A5 had a significant influence on Tac pharmacological effects for both the initial use and long-term use. The donor liver genotype and the recipient intestine genotype contribute almost equally in the short-term, but the donor genotype had a greater effect than the recipient genotype at 6 months. Personalized Tac treatment after LT should be based on the CYP3A5 genotype.
Weight of ABCB1 and POR genes on oral tacrolimus exposure in CYP3A5 nonexpressor pediatric patients with stable kidney transplant.
Almeida-Paulo G N,Dapía García I,Lubomirov R,Borobia A M,Alonso-Sánchez N L,Espinosa L,Carcas-Sansuán A J
The pharmacogenomics journal
Tacrolimus (TAC) is highly effective for the prevention of acute organ rejection. However, its clinical use may be challenging due to its large interindividual pharmacokinetic variability, which can be partially explained by genetic variations in TAC-metabolizing enzymes and transporters. The aim of this study was to evaluate the influence of genetic and clinical factors on TAC pharmacokinetic variability in 21 stable pediatric renal transplant patients. This study was nested in a previous Prograf to Advagraf conversion clinical trial. CYP3A5, ABCB1 and two POR genotypes were assessed by real-time PCR. The impact on TAC pharmacokinetics of individual genetic variants on CYP3A5 nonexpressors was evaluated by genetic score. Explicative models for TAC AUC C and C after Advagraf were developed by linear regression. The built genetic scores explain 13.7 and 26.5% of the total AUC and C total variability, respectively. Patients genetic information should be considered to monitorizate and predict TAC exposure.
The correlation between the expression of genes involved in drug metabolism and the blood level of tacrolimus in liver transplant receipts.
Wang Jianhai,Li Keqiu,Zhang Xiaoning,Teng Dahong,Ju Mingyan,Jing Yaqing,Zhao Yuxia,Li Guang
Immunosuppressive medications, such as tacrolimus and mycophenolate mofetil, are commonly used for reducing the risk of organ rejection in receipts of allogeneic organ transplant. The optimal dosages of these drugs are required for preventing rejection and avoiding toxicity to receipts. This study aimed to identify the correlation between the expression profiling of genes involved in drug metabolism and the blood level of tacrolimus in liver transplant receipts. Sixty-four liver transplant receipts were enrolled in this retrospective study. Receipts were divided into low (2-5.9 ng/ml) and high (6-15 ng/ml) tacrolimus groups. Clinical assessment showed that the blood level of tacrolimus was inversely correlated with the liver function evaluated by blood levels of total bilirubin and creatinine. Compared to the high tacrolimus group, expression levels of six cytochrome P450 enzymes, CYP1A1, CYP2B6, CYP3A5, CYP4A11, CYP19A1, and CYP17A1 were significantly higher in the low tacrolimus group. The expression levels of these genes were negatively correlated with the tacrolimus blood level. Enzyme assays showed that CYP3A5 and CYP17A1 exerted direct metabolic effects on tacrolimus and mycophenolate mofetil, respectively. These results support clinical application of this expression profiling of genes in drug metabolism for selection of immunosuppressive medications and optimal dosages for organ transplant receipts.
The calcineurin regulatory subunit polymorphism and the treatment efficacy of tacrolimus for idiopathic membranous nephropathy.
Zhu Ying,Zhang Min,Wang Fan,Lu Jianda,Chen Ruiying,Xie Qionghong,Sun Jing,Xue Jun,Hao Chuanming,Lin Shanyan
Tacrolimus is considered to be one of the main therapeutic options for idiopathic membranous nephropathy (IMN). This study aimed to investigate the association of variants in genes encoding the binding protein and the drug target (calcineurin) of tacrolimus with the efficacy in IMN patients and the potential mechanism. Sixty-seven IMN patients treated with tacrolimus were enrolled retrospectively. Sanger sequencing was performed to search for variants in all exons of the genes in 8 IMN patients and genotype for the detected variants in the other 59 patients. The molecular mechanism underlying the relationship between the variants and the efficacy was explored in human peripheral blood mononuclear cells (PBMCs) and other cell lines. Single nucleotide polymorphism rs875 (T > C) in the 3'untranslated region (3'UTR) of PPP3R1 encoding calcineurin regulatory subunit was found to be associated with the treatment efficacy of tacrolimus for IMN. Patients carrying TT genotype had a significantly higher remission rate than those carrying TC/CC genotype (83% vs. 47%, P = 0.008). Western blot showed that the TT genotype carriers exhibited reduced PPP3R1 protein levels in PBMCs (P = 0.02). Compared with C allele, T allele displayed increased binding affinity for miR-582-5p in the luciferase reporter assay (P < 0.001). Moreover, knockdown of PPP3R1 in Jurkat T cell line enhanced the immunosuppressive effect of tacrolimus. Our study revealed the association of PPP3R1 3'UTR polymorphism rs875 with the efficacy of tacrolimus in IMN patients. The functional polymorphism might alter PPP3R1 expression via modulating the interaction of miR-582-5p with PPP3R1, which further affected the immunosuppressive effect of tacrolimus.
Correlation between pharmacokinetics of tacrolimus and pharmacodynamics on NFAT-regulated gene expression in stable kidney transplant recipients
Keller Frieder,Sommerer Claudia,Giese Thomas,Zeier Martin,Schröppel Bernd
Gene expression regulated by the transcription factor NFAT (nuclear factor of activated T-cells) has been proposed for monitoring the pharmacodynamic effect of calcineurin inhibitors. We aimed to correlate the pharmacokinetics of tacrolimus with the suppression of NFAT-regulated gene expression. Tacrolimus trough (C<sub>trough</sub>) and peak concentrations (C<sub>peak</sub>) were measured by LC-MS. The effect on NFAT-regulated gene expression at trough (E<sub>trough</sub>) and at peak levels (E<sub>peak</sub>) were determined by qRT-PCR. The pharmacodynamic concentration producing the half-maximum effect (CE<sub>50</sub>) and the Hill coefficient (H) were estimated from E<sub>trough</sub> and from E<sub>peak</sub>. Ten stable kidney transplant recipients on triple immunosuppression with prednisolone, mycophenolate, and tacrolimus were analyzed. Median age was 58 years, median time since transplant was 84 months, and median serum creatinine was 249 µmol/L. The immunosuppressive effect on NFAT-regulated genes at trough concentrations was 38% (E<sub>trough</sub>), and the effect at peak concentrations was 59% (E<sub>peak</sub>) of maximum immunosuppression (E<sub>max</sub>). The pharmacodynamic parameters of the action of tacrolimus were estimated with the Hill coefficient H at 1.5 and the CE50 at 6.7 ng/mL. Accordingly, the pharmacodynamic threshold concentration was estimated at 0.9 ng/mL and the ceiling concentration at 48 ng/mL, indicating a wide span between target trough and peak levels. The low Hill coefficient indicates concentration-dependent pharmacodynamics of tacrolimus on NFAT transcripts. Therefore, the extension of the administration interval to 24 hours is not likely to jeopardize the immunosuppressive effect of the prolonged-release tacrolimus preparations.
NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation.
Bremer Sara,Vethe Nils T,Skauby Morten,Kasbo Margrete,Johansson Elisabet D,Midtvedt Karsten,Bergan Stein
British journal of clinical pharmacology
AIMS:Despite pharmacokinetic monitoring of calcineurin inhibitors, the long-term outcome after transplantation (Tx) is still hampered by the side effects of these drugs. The aim of the present study was to characterize nuclear factor of activated T cells (NFAT)-regulated gene expression as a potential pharmacodynamic biomarker for further individualization of tacrolimus (Tac) therapy. METHODS:In 29 renal allograft recipients, samples were drawn once pre-Tx, and before and 1.5 h after Tac dosing at approximately 1 week, 6 weeks and 1 year post-Tx. Tac concentrations were measured by immunoassay, while the expression of genes encoding NFAT-regulated cytokines [interleukin 2 (IL2), interferon gamma (IFNG), colony stimulating factor 2 (CSF2)] and cytochrome P450 3A5 (CYP3A5) genotyping were determined by real-time polymerase chain reaction. RESULTS:The cytokine response after Tac dosing varied up to 46-fold between patients and changed significantly with time post-engraftment. Tac concentrations 1.5 h postdose (C ) >15 μg l were associated with strong cytokine inhibition and residual gene expression (RGE) ≤10%, while lower Tac C resulted in more variable responses (RGE 2.5-68.7%). Patients with ongoing subclinical acute rejection (n = 5) demonstrated limited cytokine inhibition (RGE 39.7-72.6%), while patients with polyoma virus viraemia (n = 3) had relatively strong inhibition of cytokines (RGE 2.5-32.5%). By contrast, there was no association between Tac exposure and rejection or viraemia. CONCLUSIONS:The findings of our study support the potential of NFAT-regulated gene expression measurements as a pharmacodynamic tool for additional monitoring of Tac therapy, especially in the context of overimmunosuppression and viraemia.