Marked species differences in the bioavailability of midazolam in cynomolgus monkeys and humans.
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.
Sakuda
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S
Analysis & Pharmacokinetics Research Laboratories, Astellas Pharma, Inc., Tsukuba, Japan. shuuichi.sakuda@jp.astellas.com
Akabane
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T
Teramura
T
T