Investigation of the intestinal permeability and first-pass metabolism of drugs in cynomolgus monkeys using single-pass intestinal perfusion.
To clarify the causes of low oral bioavailability (BA) of drugs in cynomolgus monkeys, the experimental method to evaluate the drug permeability and the metabolism in the intestine of cynomolgus monkeys was established. An in situ intestinal perfusion method was performed with blood sampling from both portal and peripheral veins to calculate the intestinal permeability and the metabolism of drugs simultaneously. In all experiments, antipyrine was co-perfused with test drugs as a non-metabolized reference to calculate the individual portal vein blood flow. The effective permeability coefficient (P(eff)) of acetaminophen and piroxicam were high, and the fraction of dose absorbed from the gastrointestinal tract (Fa) thought to be 1. The intestinal availability (Fg) of acetaminophen and piroxicam were calculated to be 0.39 and 1.09, respectively. The Fa*Fg values of these drugs calculated from the perfusion study almost coincided with those obtained from the in vivo PK analysis in the previous report. In addition, the Fg values of verapamil and midazolam were calculated as 0.16 and 0.26, respectively, suggesting these drugs were metabolized extensively in the intestine after oral administration to cynomolgus monkey. Furthermore, the Fg values of these drugs were increased to 0.8-0.85 in the presence of 1-aminobenzotriazole, a typical cytochrome P450 (CYP) inhibitor. In conclusion, it was clarified that acetaminophen, verapamil and midazolam were metabolized extensively in the intestine of cynomolgus monkeys. This intestinal perfusion method is considered to be useful to identify the factors of species difference in the oral absorption of drugs.
Takahashi
Masayuki
M
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi-Sankyo Co., Ltd., Tokyo, Japan. takahashi.masayuki.c8@daiichisankyo.co.jp
Washio
Takuo
T
Suzuki
Norio
N
Igeta
Katsuhiro
K
Yamashita
Shinji
S
D000284:Administration, Oral; D000818:Animals; D000983:Antipyrine; D001682:Biological Availability; D065607:Cytochrome P-450 Enzyme Inhibitors; D008658:Inactivation, Metabolic; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008252:Macaca fascicularis; D010477:Perfusion / Q000379:methods; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D012016:Reference Values; D014230:Triazoles
D065607:Cytochrome P-450 Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D014230:Triazoles; C033020:1-aminobenzotriazole; D000983:Antipyrine