Acyl-Glucuronide and Acyl-Glutathione The Effects of 1-Aminobenzotriazole Inhibition on the Formation of Metabolites in Rat Hepatocytes
1-Aminobenzotriaole (ABT) is a commonly used non-selective mechanism based human and non-human cytochrome P450 (P450) inactivator. However, the direct effects of ABT mediated P450 inhibition on conjugative metabolism, specifically acyl-glucuronide and acyl-glutathione formation has not been previously investigated. In the present study, we evaluated the in vitro effects of ABT induced inhibition of P450 metabolism on the formation of 1-O-acyl-glucuronides of the carboxylic acid-containing drugs gemfibrozil (GEM), tolmetin (TOL), mefenamic acid (MFA), and diclofenac (DCF), and the S-acyl-glutathione formation of MFA and DCF in rat hepatocytes. In vitro incubations of each carboxylic acid-containing drug (100 μM) separately in rat hepatocytes preincubated (30 min) with ABT (500 μM), resulted in 12.7%, 30%, 37%, and 40% increases in the formation of 1-O-acyl-glucuronides at the 30 min time point for GEM, TOL, MFA, and DCF, respectively.
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