Species Differences in Mechanism-Based Inactivation of CYP3A in Humans, Rats and Mice

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Abstract
Mechanism-based inactivation (MBI) of cytochrome P450 3A (CYP3A) often causes serious drug-drug interactions. To examine species differences in MBI of CYP3A between humans and rodents, we compared MBI potencies of five representative CYP3A inhibitors in human, rat and mouse liver microsomes. Among the inhibitors studied, erythromycin and clarithromycin exhibited markedly weaker MBI effects on CYP3A activity in rat and mouse liver microsomes compared to human liver microsomes. Results of spectroscopic experiments showed that erythromycin and clarithromycin form a metabolic intermediate complex with human liver microsomes but not with rat or mouse liver microsomes. In contrast, troleandomycin, diltiazem and nicardipine form a metabolic intermediate complex with rat and mouse liver microsomes, although some differences in MBI potency among species were observed. Parameters for MBI potency (k(inact)/K(I) ratio) and reversible inhibition (IC(50)) were negatively correlated (r=-0.820, p=0.0003), suggesting that the different affinities of CYP3A inhibitor for CYP3A may partly contribute to the different MBI potencies of inhibitor among species. Taken together, the results suggest that there are species differences in MBI of CYP3A in humans, rats and mice, which should be considered when rodents are used as in vivo models for MBI-mediated drug-drug interaction study.
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