Age-related changes of hepatic clearances of cytochrome P450 probes, midazolam and R-/S-warfarin in combination with caffeine, omeprazole and metoprolol in cynomolgus monkeys using in vitro–in vivo correlation

Abstract

1. Pharmacokinetics of human cytochrome P450 probes (caffeine, racemic warfarin, omeprazole, metoprolol and midazolam) were investigated after single intravenous and oral administrations at doses of 0.20 and 1.0 mg kg⁻¹, respectively, in combination to three young (3-year-old) and three aged (16-year-old) cynomolgus monkeys.

2. The plasma concentrations of caffeine and R-/S-warfarin decreased slowly in a monophasic manner, but those of omeprazole, metoprolol and midazolam decreased rapidly, in a similar manner to those as reported for pharmacokinetics in humans.

3. The mean maximum concentrations of R- and S-warfarin (4.6 and 3.7 µg/mL, respectively) in aged monkeys after oral administration were significantly higher than those in young monkeys (3.3 and 2.7 µg/mL). The mean clearance (CL) values of midazolam in aged monkeys (9.5 mL/min/kg) were significantly lower than those in young monkeys (13 mL/min/kg).

4. Individual intrinsic CL values for omeprazole (r = 0.29) and metoprolol (r = 0.30) of individual monkey livers were inversely correlated with their ages significantly (p < 0.05) in liver microsomes prepared from 55 cynomolgus monkeys.

5. These results suggest that cynomolgus monkeys could be a good model for humans, especially with particular characteristics in reduced CLs of some human P450 substrates by aging.

• Cynomolgus monkey
• hepatic clearance
• in vitro–in vivo correlation
• liver microsomes, P450 substrates

Acknowledgements

We would like to thank Kenichi Nunoya, Yasuka Matsumoto, Masanori Shukuya and Misaki Yogo for their support in this study.

Declaration of interest

The authors report no declarations of interest. The authors are responsible for the content and writing the article.

This work was supported, in part, by the Takeda Science Foundation (H. Y.).