Simultaneous pharmacokinetics evaluation of human cytochrome P450 probes, caffeine, warfarin, omeprazole, metoprolol and midazolam, in common marmosets (Callithrix jacchus)

Abstract

1. Pharmacokinetics of human cytochrome P450 probes (caffeine, racemic warfarin, omeprazole, metoprolol and midazolam) composite, after single intravenous and oral administrations at doses of 0.20 and 1.0 mg kg⁻¹, respectively, to four male common marmosets were investigated.

2. The plasma concentrations of caffeine and warfarin decreased slowly in a monophasic manner but those of omeprazole, metoprolol and midazolam decreased extensively after intravenous and oral administrations, in a manner that approximated those as reported for pharmacokinetics in humans.

3. Bioavailabilities were ∼100% for caffeine and warfarin, but <25% for omeprazole and metoprolol. Bioavailability of midazolam was 4% in marmosets, presumably because of contribution of marmoset P450 3A4 expressed in small intestine and liver, with a high catalytic efficiency for midazolam 1′-hydroxylation as evident in the recombinant system.

4. These results suggest that common marmosets, despite their rapid clearance of some human P450 probe substrates, could be an experimental model for humans and that marmoset P450s have functional characteristics that differ from those of human and/or cynomolgus monkey P450s in some aspects, indicating their importance in modeling in P450-dependent drug metabolism studies in marmosets and of further studies.

• CYP3A4
• hepatic clearance
• human
• marmoset
• P450 substrates

Acknowledgements

The authors thank Norie Murayama, Takako Suzuki, Mirai Kawano and Masayuki Mogi for their supports of this study.

Declaration of interest

This work was supported in part by Grant-in-Aid for Scientific Research and also resulted from “Construction of System for Spread of Primate Model Animals” under the Strategic Research Program for Brain Sciences of Japan Agency for Medical Research and Development. The authors are responsible for the content and writing the article and report no declarations of interest.