Please use this identifier to cite or link to this item: https://doi.org/10.2174/187231208785425791
Title: Oxidative bioactivation and toxicity of leflunomide in immortalized human hepatocytes and kinetics of the non-enzymatic conversion to its major metabolite, A77 1726
Authors: Seah, Q.M.
New, L.-S. 
Chan, E.C.Y. 
Boelsterli, U.A.
Keywords: A77 1726
Bioactivation
Hepatotoxicity
Human hepatocytes
Leflunomide
Issue Date: Aug-2008
Citation: Seah, Q.M.,New, L.-S.,Chan, E.C.Y.,Boelsterli, U.A. (2008-08). Oxidative bioactivation and toxicity of leflunomide in immortalized human hepatocytes and kinetics of the non-enzymatic conversion to its major metabolite, A77 1726. Drug Metabolism Letters 2 (3) : 153-157. ScholarBank@NUS Repository. https://doi.org/10.2174/187231208785425791
Abstract: We used immortalized human hepatocytes to study the bioactivation of leflunomide and the metabolic degradation to its major metabolite, 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 (t12a = 1.5 h, t1/2 b >24 h), but much slower in cell-free medium (t1/2 >24 h). In contrast, the generation of A77 1726 occurred at a similar rate in cells and cell-free systems. In conclusion, leflunomide was rapidly metabolized in human hepatocytes to A77 1726, but its toxicity was dependent on other, CYP-dependent intermediates. © 2008 Bentham Science Publishers Ltd.
Source Title: Drug Metabolism Letters
URI: http://scholarbank.nus.edu.sg/handle/10635/106191
ISSN: 18723128
DOI: 10.2174/187231208785425791
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