Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-glycoprotein (P-gp), multidrug resistance associated protein (MRP) and breast cancer resistance protein (BCRP) in conjunction with metabolizing enzymes (cytochrome P450, CYP450) are major factors in such interaction. In recent years, a large number of studies have shown that P-gp plays a role in the oxidative metabolism of its substrates that are also substrates of CYP3A4. Combined actions of P-gp and CYP3A could account in some part for the low oral bioavailability determined for many of these dual substrates. P-gp along with efflux transporters (MRP and BCRP) having overlapping substrate specificity plays critical role in drug disposition. The relationship between MRP or BCRP and CYP3A is similar to that between P-gp and CYP3A. In this paper, we summarize the classification of efflux transporters, the main metabolizing enzymes CYP3A, clinical significance interactions mediated by efflux transporters and CYP450 enzymes and in vitro studies.

The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme (CYP3A4), which is the most important human drug-metabolizing enzyme. In addition, PXR is supposed to be involved both in basal and/or inducible expression of many other CYPs, such as CYP2B6, CYP2C8, 2C9 and 2C19, CYP3A5, CYP3A7, and CYP2A6. Interestingly, the dynamics of PXR-mediated target genes regulation has not been systematically studied and we have only a few mechanistic mathematical and biologically based models describing gene expression dynamics after PXR activation in cellular models. Furthermore, few indirect mathematical PKPD models for prediction of CYP3A metabolic activity in vivo have been built based on compartmental models with respect to drug⁻drug interactions or hormonal crosstalk. Importantly, several negative feedback loops have been described in PXR regulation. Although current mathematical models propose these adaptive mechanisms, a comprehensive mathematical model based on sufficient experimental data is still missing. In the current review, we summarize and compare these models and address some issues that should be considered for the improvement of PXR-mediated gene regulation modelling as well as for our better understanding of the quantitative and spatial dynamics of CYPs expression.

BACKGROUND & OBJECTIVE:Abnormal expression and activation of epidermal growth factor receptor (EGFR), which is closely related to the recurrence and poor prognosis of ovarian cancer, can promote chemotherapy resistance of tumor cells. Lung resistance protein (LRP), a multidrug resistance protein causing platinum-resistance, is an independent factor in predicting chemotherapy sensitivity to ovarian cancer. This study was to explore the correlations of EGFR and LRP to chemotherapy resistance and prognosis of ovarian cancer. METHODS:Expressions of EGFR and LRP in 76 specimens of ovarian malignant tumor, nine borderline tumor, 17 benign tumor and 15 normal ovary were studied using immunohistochemistry. Patients with ovarian cancer were followed up. Correlations of EGFR and LRP to chemotherapy efficacy and survival time of patients with ovarian cancer after operation were analyzed. RESULTS:The positive rates of EGFR and LRP in malignant specimens (73.68% and 71.79%) were significantly higher than those in normal and benign ones (P <0.01). EGFR was highly expressed in ovarian cancer patients at late stage (III-IV), with poor differentiation and ascites (P <0.05). The short-term efficacy rates of ovarian cancer were lower in patients with positive expressions of EGFR and LRP (57.14% and 53.70%) than in those with negative expressions (P<0.05). The positive rates of EGFR and LRP were significant higher in patients with chemotherapy resistance (92.86% and 85.71%) than in those sensitive to chemotherapy (P<0.05). The three-year survival rate of ovarian cancer patients was 53.00%. Patients with positive EGFR and LRP and poor short-term efficacy after chemotherapy had short survival time (P<0.01). CONCLUSION:The expression of EGFR and LRP could be used to predict chemotherapy resistance and prognosis of ovarian cancer.