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Cynomolgus monkeys [Macaca fascicularis (mf)] are widely used to determine pharmacokinetics and toxicological potential of many drug candidates as human models in the drug discovery and development. Cytochrome P450s (P450, CYP), one of the most important enzymes in drug metabolism, in monkey livers are generally similar to corresponding human P450s exhibiting high degrees of homologies in cDNAs and amino acid sequences. Species differences regarding important liver P450 3A and 2D function were examined between cynomolgus monkeys and humans using typical human P450 probe reactions using midazolam (a P450 3A marker), dextromethorphan and bufuralol (P450 2D markers). P450 3A-mediated midazolam 1'-hydroxylation activities in liver microsomes from individual monkey were highly correlated with midazolam 4'-hydroxylation activities but not correlated with dextromethorphan N-demethylation activities. Recombinant monkey CYP2D17 and CYP2D44 catalyzed dextromethorphan O- and N-demethylations as well as monkey mfCYP3A4 and mfCYP3A5 did. On the other hand, contributions of corresponding P450 2D6 and P450 3A4/5 to dextromethorphan N- and O-demethylations, in human liver microsomes were negligible under the present conditions. From these results, monkey P450 2D and 3A enzymes might have broader substrate specificity toward dextromethorphan oxidation than those in human livers. Special attention should be paid when enzymatic and pharmacokinetic data are extrapolated from monkeys to humans.

Species Difference between Cynomolgus Monkeys and Humans on Cytochromes P450 2D and 3A-Dependent Drug Oxidation Activities in Liver Microsomes