Identification of putative substrates for cynomolgus monkey cytochrome P450 2C8 by substrate depletion assays with 22 human P450 substrates and inhibitors

Abstract

Cynomolgus monkeys are widely used in drug developmental stages as non-human primate models. Previous studies used 89 compounds to investigate species differences associated with cytochrome P450 (P450 or CYP) function that reported monkey specific CYP2C76 cleared 19 chemicals, and homologous CYP2C9 and CYP2C19 metabolized 17 and 30 human CYP2C9 and/or CYP2C19 substrates/inhibitors, respectively. In the present study, 22 compounds selected from viewpoints of global drug interaction guidances and guidelines were further evaluated to seek potential substrates for monkey CYP2C8, which is highly homologous to human CYP2C8 (92%). Amodiaquine, montelukast, quercetin and rosiglitazone, known as substrates or competitive inhibitors of human CYP2C8, were metabolically depleted by recombinant monkey CYP2C8 at relatively high rates. Taken together with our reported findings of the slow eliminations of amodiaquine and montelukast by monkey CYP2C9, CYP2C19 and CYP2C76, the present results suggest that these at least four chemicals may be good marker substrates for monkey CYP2C8. Copyright © 2016 John Wiley & Sons, Ltd.

Utility of non-human primates in drug development: Comparison of non-human primate and human drug-metabolizing cytochrome P450 enzymes

“…On the other hand, cynomolgus monkey P450 2C76, which has no ortholog in humans, shows lower amino acid sequence identity to any human P450 2C forms [12]. Because a broad evaluation of potential substrates for cynomolgus monkey P450 2C enzymes was not conducted, to obtain the comprehensive information of substrate selectivity for major cynomolgus monkey P450 2C enzymes, 89 commercially available drugs were investigated [13][14][15][16]. Cynomolgus monkey P450 2C19 metabolized 34 of the 89 compounds, including representative human P450 2C19 substrates such as diazepam and omeprazole and human P450 2C9 substrates such as diclofenac, warfarin, and flurbiprofen [15].…”