Effects of perphenazine, diazepam and nitrazepam on amitriptyline metabolism in rat

Repeated coadministration of amitriptyline (AMT) and perphenazine (PPZ) decreased the AMT-induced increase of hepatic microsomal aminopyrine N-demethylase, aniline hydroxylase, NADPH-cytochrome c reductase and UDP-glucuronyltransferase (UDP-GT) activities in rats. This may be explained by a fact that inhibition of AMT metabolism in hepatic microsomes by PPZ led to increase the non-conjugated formation of AMT and its metabolites in the liver, brain, urine and feces. On the other hand, a slight decrease of drug metabolizing enzyme activity by diazepam (DZP) but not by nitrazepam (NTZ) was enhanced by combined treatment of AMT, whereas the enhancement of UDP-GT activity by DZP or NTZ was suppressed by coadministration of AMT. At the same time there was no clear increase of non-conjugated formation of AMT metabolites in rat urine and feces during combined treatment.