title: Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey.
abstract: Oral bioavailability of some drugs is substantially lower in cynomolgus monkeys than in various other species, including humans. In the present study, midazolam was used as a model drug to investigate the reason for the lower bioavailability in these monkeys. The bioavailability of midazolam after oral administration was minimal in monkeys and rats, being only 2.1 and 1.1%, respectively. In monkeys, this low bioavailability could not be explained simply in terms of a hepatic first-pass effect. To examine the roles of intestinal metabolism and transport, we evaluated apical-to-basal and basal-to-apical transport of midazolam, and the formation of metabolites in small intestinal tissues using an Ussing-type chamber. The values of mucosal extraction ratio were estimated to be 0.97, 0.93, and 0.89 during apical-to-basal transport in the upper, middle, and lower small intestine of monkeys, respectively, whereas the corresponding values for rats were close to zero, indicating that extensive metabolism of midazolam occurs, particularly in the upper region of the small intestine in monkeys, but not rats. Interestingly, formation of the metabolites was much greater during transport in the apical-to-basal direction than in the basal-to-apical direction, and this could be well explained by a mathematical model based on the assumption that extensive metabolism is associated with the uptake process of midazolam from the apical cell surface. Thus, we conclude that an asymmetric distribution of metabolic activity in the small intestine, leading to extensive metabolism during uptake from the apical cell surface, accounts for the minimal oral bioavailability of midazolam in cynomolgus monkeys.
authors.affiliation: Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishimura
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amano
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kubo
authors.forename: Midori
authors.initials: M
authors.lastname: Ono
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujita
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kimura
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004285:Dogs; D004386:Duodenum / Q000201:enzymology / Q000378:metabolism; D018757:GABA Modulators / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D007082:Ileum / Q000201:enzymology / Q000378:metabolism; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000378:metabolism*; D007583:Jejunum / Q000201:enzymology / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D018757:GABA Modulators; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam