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Rat liver slices and diazepam metabolism: in vitro interactions with volatile anaesthetic drugs and albumin. Dale O,Gandolfi A J,Brendel K,Schuman S British journal of anaesthesia The influence of the volatile anaesthetic agents enflurane, isoflurane, halothane and the halothane metabolite trifluoroacetic acid was studied on the hepatic elimination of diazepam, by incubating precision-cut slices of rat liver in a closed system. The impact of anaesthetic-induced action on enzyme activity and diazepam binding to human serum albumin (HSA) was assessed in protein free and protein containing buffers, respectively. Human serum albumin reduced the elimination of diazepam by 12 and 50% at concentrations of 1 and 10 mg ml-1, respectively. In the absence of albumin, halothane 1 mmol litre-1 reduced the elimination of diazepam by 13%, whereas enflurane at 1.5 mmol litre-1 caused a reduction of 8%. No effect was seen from isoflurane 1 mmol litre-1 and trifluoroacetic acid 4 mmol litre-1. In the presence of the highest concentration of albumin, however, an increased elimination of diazepam of 24% resulted from exposure to enflurane and trifluoroacetic acid, while no statistically significant changes were seen for isoflurane and halothane. The present work supports the view that volatile anaesthetic agents may cause pharmacokinetic drug interactions by interference with both enzyme activity and drug protein binding. 10.1093/bja/60.6.692
Toxic actions of the metabolites of halothane: LD 50 and some metabolic effects of trifluoroethanol and trifluoroacetic acid in mice and guinea pigs. Airaksinen M M,Tammisto T Annales medicinae experimentalis et biologiae Fenniae
Mammalian toxicity of trifluoroacetate and assessment of human health risks due to environmental exposures. Archives of toxicology While trifluoroacetic acid has limited technical uses, the highly water-soluble trifluoroacetate (TFA) is reported to be present in water bodies at low concentrations. Most of the TFA in the environment is discussed to arise from natural processes, but also with the contribution from decomposition of environmental chemicals. The presence of TFA may result in human exposures. For hazard and risk assessment, the mammalian toxicity of TFA and human exposures are reviewed to assess the margin of exposures (MoE). The potential of TFA to induce acute toxicity is very low and oral repeated dose studies in rats have identified the liver as the target organ with mild liver hypertrophy as the lead effect. Biomarker analyses indicate that TFA is a weak peroxisome proliferator in rats. TFA administered to rats did not induce adverse effects in an extended one-generation study and in a developmental toxicity study or induce genotoxic responses. Based on recent levels of TFA in water and diet, MoEs for human exposures to TFA are well above 100 and do not indicate health risks. 10.1007/s00204-023-03454-y
2,2,2-Trifluoroethanol intestinal and bone marrow toxicity: the role of its metabolism to 2,2,2-trifluoroacetaldehyde and trifluoroacetic acid. Fraser J M,Kaminsky L S Toxicology and applied pharmacology 2,2,2-Trifluoroethanol (TFE) produces bone marrow and small intestine toxicity resulting in leukopenia, loss of intestinal dry weight, and consequent lethal septicemia in male Wistar rats. Its metabolic pathway, based on serum and small intestine time courses of substrate and metabolites, was determined to be TFE in equilibrium 2,2,2-trifluoroacetaldehyde (TFAld)----trifluoroacetic acid (TFAA). Administered TFE and TFAld were not toxic per se, since their toxicity and metabolism were inhibited by pyrazole. TFE and TFAld were equipotent at equimolar doses thus precluding the oxidative reaction, TFE to TFAld, from being the toxic step. Since equimolar TFAA exhibited no toxic effects, an oxidative intermediate on the pathway from TFAld to TFAA, most likely F3C-C+(OH)2, must thus be the toxic moiety. The intermediate TFAld is stable in serum, as determined by a novel assay developed for its analysis in biological systems, and can be transported to the target tissues, bone marrow, and small intestine, after formation probably in the liver. On the basis of the more rapid metabolism of TFE to higher levels of TFAld in the small intestine and bone marrow than in the serum, the closer correspondence of bone marrow and small intestine metabolite ratios than serum ratios at high and low doses of TFE to the corresponding ratios of toxicity, and the decreased toxicity of TFAld when administered ig versus ip, the formation of the toxic metabolic intermediate of TFE probably occurs in the target tissues.