The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humans.
In order to elucidate the causes of the species differences in the oral bioavailability (BA) between cynomolgus monkeys and humans, the contributions of first-pass metabolism and intestinal absorption were investigated. Typical substrates of cytochrome P450 enzymes, UDP-glucuronosyltransferase enzymes and efflux transporters were selected, and the BA, the hepatic availability (Fh) and the fraction dose absorbed from gastro-intestinal tract (Fa*Fg) were calculated from pharmacokinetic analysis after oral and intravenous administration in cynomolgus monkeys. In addition, in vitro metabolism was investigated using liver and intestinal microsomes to evaluate the relationship between in vivo and in vitro results. The BA of cynomolgus monkeys was low compared with that in humans with most of the drugs tested, and not only Fh but also Fa*Fg contributed significantly to the low BA in cynomolgus monkeys. When Fh was evaluated in in vitro experiments, it correlated well with the in vivo Fh. However, although the metabolic activities of CYP3A4 substrates were high in cynomolgus monkey intestinal microsomes, those of the other substrates were low or not detected. These findings suggested that the species differences and low BA in cynomolgus monkeys could be mostly attributed not only to hepatic first-pass metabolism but also to the intestinal absorption process.
Takahashi
Masayuki
M
Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi-Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. takahashi.masayuki.c8@daiichisankyo.co.jp
Washio
Takuo
T
Suzuki
Norio
N
Igeta
Katsuhiro
K
Yamashita
Shinji
S
D000818:Animals; D001682:Biological Availability; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D008861:Microsomes / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013045:Species Specificity
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System