Marked species differences in the bioavailability of midazolam in cynomolgus monkeys and humans

Abstract

The bioavailability (F) of midazolam in cynomolgus monkeys (0.02) was markedly lower than that in humans (0.24–0.46) and the reason for this difference in F between the two species was investigated. Based on the area under the plasma concentration–time curve after intravenous and intraportal infusion to cynomolgus monkeys, the hepatic availability (F_h) was estimated as 0.66. The fraction of dose absorbed (F_a) estimated from the single-pass intestinal perfusion method was 1.0 in cynomolgus monkeys. The intestinal availability (F_g = F/F_a/F_h) was calculated as 0.03 in cynomolgus monkeys. Since the F_a of midazolam has been reported to be almost 1.0 in humans, F_h and F_g were calculated as 0.33–0.76 and 0.46–1.00 when the reference values for hepatic blood flow (1026–1530 ml h⁻¹ kg⁻¹) were used. In conclusion, the main reason for low F in cynomolgus monkeys was the markedly higher first-pass intestinal metabolism seen in cynomolgus monkeys compared with humans.

Key words::

• Midazolam
• monkey
• intestinal perfusion
• intestinal availability
• species differences

Acknowledgement

The authors thank Shin Nippon Biomedical Laboratories Ltd. for technical support.