Abstract

To clarify species differences in the pharmacokinetic parameters of cytochrome P450 (CYP) activities between humans and experimental animals, we assessed several CYP activities in mice, rats, dogs, monkeys, and microminipigs, using the simultaneous administration of typical human CYP substrates, such as caffeine (human CYP1A2 substrate), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A), to these animals. The intrinsic clearance (CLint) of these 5 substrates was also examined using the liver microsomes of humans and the experimental animals. The high bioavailabilities (BAs) and low CLint values of caffeine in the experimental animals were similar to those in humans. Mice and monkeys had lower BAs and higher CLint values of losartan than those in humans. Mice, rats, and monkeys had lower BAs and higher CLint values of omeprazole than those in humans. The lowest BAs of dextromethorphan were observed in monkeys and microminipigs, and only the CLint in dogs was similar to that in humans. The BA of midazolam in microminipigs only was similar to that in humans, while the CLint values in the other animals were similar to that in humans. These results indicated that in vitro and in vivo experimental data obtained using multiple animals including microminipigs are useful for predicting human pharmacokinetics.

Highlights

  • The cytochrome P450s (CYPs) are involved in the metabolism of many endogenous compounds and xenobiotics [1,2]

  • CYP3A is most commonly described as a contributor to drug clearance in humans, followed by CYP1A2, CYP2C9, CYP2C19, and CYP2D6 (5-15%, respectively) [3]

  • Drug metabolism mediated by human CYP1A and CYP3A in their liver microsomes of these animals was reported to be similar to that of humans [12,24,25], whereas their CYP activities for CYP2D substrates were higher than human activities [12,26]

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Summary

Introduction

The cytochrome P450s (CYPs) are involved in the metabolism of many endogenous compounds and xenobiotics [1,2]. Species differences in CYP isoforms are a major cause of the differences reported in drug metabolism Experimental animals, such as mice, rats, dogs, monkeys, and minipigs, are commonly used in nonclinical studies for new drug candidates to predict pharmacokinetic profiles in humans. Species differences in CYP activities, which have been reported in a number of studies, need to be clarified between experimental animals and humans Humans and rodents, such as mice and rats, generally exhibit greater species differences in CYP activities; rodents have frequently been used as animal models in drug discovery [411]. Drug metabolism mediated by human CYP1A and CYP3A in their liver microsomes of these animals was reported to be similar to that of humans [12,24,25], whereas their CYP activities for CYP2D substrates were higher than human activities [12,26].

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