Metabolism of metronidazole and antipyrine in hepatocytes isolated from mouse and rat.

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 Km values for the formation of the major metronidazole metabolites ranged from 0.6 to 3 mM. The intrinsic clearance values (Vmax/Km) of metronidazole to the acetic acid, hydroxy and glucuronide metabolites were 58 (36-125) and 21 (12-28; P less than 0.05), 156 (63-263) and 36 (19-56; P less than 0.05), and 269 (102-452) and 500 (389-1616; P less than 0.05) nl/min per 10(6) hepatocytes, for mouse and rat, respectively (median with range, n = 6). 3. The average Km values for the formation of antipyrine metabolites ranged from 2 to 10 mM. The intrinsic clearance values for production of 3-hydroxymethyl-, nor- and 4-hydroxyantipyrine were 232 (43-519) and 487 (296-793; P less than 0.05), 594 (168-813) and 93 (55-180; P less than 0.05), and 118 (23-505) and 239 (134-501; P greater than 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.