Metabolism of metronidazole and antipyrine in hepatocytes isolated from mouse and rat
Abstract
1. In order to study species-related differences and select a model for the human metabolism of metronidazole and antipyrine, the Michaëlis-Menten kinetics of metabolite formation from the two compounds were investigated in freshly isolated mouse and rat hepatocytes. 2. The average K m values for the formation of the major metronidazole metabolites ranged from 0.6 to 3 mM. The intrinsic clearance values ( V max / K m ) of metronidazole to the acetic acid, hydroxy and glucuronide metabolites were 58 (36-125) and 21 (12-28; P <0.05), 156 (63-263) and 36 (19-56; P <0.05), and 269 (102-452) and 500 (389-1616; P <0.05)nl/min per 10 6 hepatocytes, for mouse and rat, respectively (median with range, n =6). 3. The average K m values for the formation of antipyrine metabolites ranged from 2 to 10mM. The intrinsic clearance values for production of 3-hydroxymethyl-, nor- and 4-hydroxyantipyrine were 232 (43-519) and 487 (296-793; P <0.05), 594 (168-813) and 93 (55-180; P <0.05), and 118 (23-505) and 239 (134-501; P >0.05)nl/min per 10 6 hepatocytes, for mouse and rat, respectively (median with range, n =6). 4. The results demonstrate that metronidazole and antipyrine are metabolized with quantitative, but not qualitative, differences in isolated hepatocytes from mice and rats. Neither species provided an ideal model for the human metabolism of the two compounds.