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Oxidative Bioactivation and Toxicity of Leflunomide in Immortalized Human Hepatocytes and Kinetics of the Non-Enzymatic to Its Major etabolitie, A77 1726

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We used immortalized human hepatocytes to study the bioactivation of leflunomide and the metabolic degradation to its major metabolic,A77 1726. Both leflunomide and A77 1726 caused a time-and concentration-dependent increase in LDH release. The cytotoxicity of leflunomide,but not that of A77 1726, was prevented by the pan -CYP inhibitor, 1-aminobenzotriazole,indicating that an oxidative metabolite(s) was responsible for the cell injury.LC/MS/MS analysis revealed that leflunomide was rapidly degraded in hepatocytes biphasically(t1/2a=1.5 h,t1/2b>24h),but much slower in cell-free medium(t1/2>24 h).In contrast,the generation of A77 1726 occured at a similar rate in cells and cell-free system s.In conclusion,leflunomide wsa rapidly metabolized in human hepatocytes to A77 1726, but its toxicity was dependent on other ,CYP-dependent intermedietly metabolized in human hepatocytes to A77 1726, but its toxicity was dependent on other ,CYP-dependent intermediidly metabolized in human hepatocytes to A77 1726, but its toxicity was dependent on other,CYP-dependent intermediidly metabolized in human hepatocytes to A77 1726,but its toxicity was dependent intermediates.

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Keywords: A77 1726; Leflunomide; bioactivation; hepatotoxicity; human hepatocytes

Document Type: Research Article

Publication date: August 1, 2008

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  • Drug Metabolism Letters publishes short papers on major advances in all areas of drug metabolism and disposition. The emphasis will be on publishing quality papers very rapidly. Letters will be processed rapidly by taking full advantage of the Internet technology for both the submission and review of manuscripts. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites, reactive intermediate and glutathione conjugates.
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