Drug metabolism and fetal toxicity: changes in fetal toxicity of aminopyrine by variation of drug metabolizing enzyme activity in mice.

The influence of hepatic drug-metabolizing enzyme activity on the fetal toxicity of aminopyrine (AM, 200 mg/kg s.c.) was examined in mice. We used the hepatic enzyme inhibitors metyrapon (40 mg/kg s.c.) and SKF-525-A (20 mg/kg s.c.), simultaneously administered with AM on days 7-9 of pregnancy. As hepatic enzyme-inducers we used 3-methyl-cholanthrene (3-MC, 2 mg/kg s.c.) and CoCl2 (40 mg/kg s.c.) were administered on days 5-7 of pregnancy followed by AM on days 7-9. The fetal toxicity of the enzyme inducers and inhibitors was not significantly different from controls. Fetal toxicity of AM (57.1%) was slightly increased and decreased by metyrapon (26.8%). Pretreatment with CoCl2 markedly increased the fetal toxicity of AM (88.6%), particularly by an increase in new abnormalities but the decrease in AM toxicity by SKF-525-A was unclear. The induction of AM N-demethylase and aniline hydroxylase activity was observed in liver microsomes from pregnant mice treated with phenobarbital and AM. From these findings, it appears that the fetal toxicity of AM was altered according to induced changes in maternal hepatic drug metabolizing enzyme activities.