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

Xenobiotica. 2006 Apr;36(4):331-40. doi: 10.1080/00498250600571749.


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.

MeSH terms

  • Administration, Oral
  • Animals
  • Area Under Curve
  • Biological Availability
  • Chromatography, Liquid
  • GABA Modulators / administration & dosage
  • GABA Modulators / blood
  • GABA Modulators / pharmacokinetics
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Liver / metabolism
  • Macaca fascicularis
  • Male
  • Midazolam / administration & dosage
  • Midazolam / blood
  • Midazolam / pharmacokinetics*
  • Models, Chemical
  • Perfusion
  • Species Specificity
  • Time Factors


  • GABA Modulators
  • Midazolam