Effects of imidazole antimycotics on the liver microsomal cytochrome P450 isoforms in rats: comparison of in vitro and ex vivo studies.

We have studied the effects of three imidazole derivatives, clotrimazole (CLO), ketoconazole (KET) and miconazole (MIC) on the liver microsomal diazepam (DZ) metabolism. In in vitro experiments using rats and human liver microsomes, significant inhibition of CYP3A in terms of DZ-3-hydroxylase activity was observed. The inhibition of DZ metabolism was seen 1 h after CLO dosing. On the other hand, the induction of certain cytochrome P450 (CYP) isozymes was observed in in vivo studies 24 h after dosing. That is, CYP1A, CYP2B and CYP3A2, but not CYP2E, were observed 24 h after CLO or KET or MIC treatment. Under these conditions, CLO was the most potent inducer of CYP3A and MIC was a more potent inducer of CYP1A and CYP2B. KET induced CYP1A and CYP2B whereas the inducibility of KET was less than those of CLO and MIC. All of the imidazole derivatives tested here showed significant inhibition of CYP isozymes which overcame the induction of the CYP isozymes by those drugs in the data of Western blot analysis.