Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H-2-receptor antagonists

The isozymes CYP1A2, CYP2D6, and CYP3A4/5 are involved in the majority of a ll cytochrome P450-mediated drug biotransformations, In this study we inves tigated the inhibition profiles of CYP1A2 (substrate: caffeine) CYP2D6 (sub strate: dextromethorphan), and CYP3A4/5 (substrate: dextrorphan) by cimetid ine, ranitidine, and the novel Hz-receptor antagonist ebrotidine in human l iver microsomes, The inhibitory effect of the drugs on the enzymes activiti es were as follows: CYP1A2: cimetidine >> ranitidine = ebrotidine; CYP2D6: cimetidine >>> ranitidine = ebrotidine; CYP3A4/5: ebrotidine > cimetidine > >> ranitidine, The inhibition of CYP3A4/5 enzyme activity by ebrotidine was competitive, To test whether the inhibitory effect of ebrotidine in CYP3A activity was also found in vivo, we analyzed the biodisposition of midazola m in 8 healthy volunteers. Midazolam biodisposition was significantly reduc ed when administered together with cimetidine (P < .05), whereas no signifi cant inhibition was observed with ebrotidine or ranitidine compared with pl acebo. Psychomotor performance analysis revealed no significant effect of t he observed reduction on midazolam biodisposition. We concluded that patien ts who are receiving treatment with drugs metabolized through CYP3A may exp erience enhanced drug effects as a result of pharmacokinetic interaction wh en treated concomitantly with cimetidine, In contrast, the effect of raniti dine or ebrotidine on CYP3A activity in vivo seems to have Little clinical significance.