title: Evaluation of factors to decrease plasma concentration of an HIV protease inhibitor, saquinavir in ethanol-treated rats.
abstract: Although alcohol consumption is a factor in which the bioavailability of saquinavir (SQV) are retarded, the cause for this phenomenon remains to be uncertain. In the presence study, we examined factors to decrease plasma concentration of SQV in ethanol-treated rats. The ethanol-treated rats were prepared by making them freely access to 15% ethanol solution for 14 d (Day 14 rats). The exsorption clearance of SQV from the blood circulation to the jejunal lumen in the Day 14 rats increased by 6-fold as compared to ethanol non-treated (NT) rats. In the presence of 25 microM ketoconazole (KCZ) or 10 microM cyclosporin A (CsA) in the jejunal lumen, the plasma concentration of SQV in the portal vein increased significantly, and this effect of 10 microM CsA was superior to that of 25 microM KCZ. The biliary excretion clearance of SQV in Day 14 rats also increased by 1.8-fold as compared to that in the NT rats. The metabolic clearance rate (V(max)/K(m)) of SQV in the intestinal microsomes from the Day 14 rats increased significantly, while in the liver microsomes the V(max)/K(m) did not change. The phase II metabolism processes in the Day 14 rats based on UDP-glucuronosyltransferases and gultathion-S-tnrasferase activities were activated, however, they were not likely to be one of factors to decrease the bioavailability of oral SQV, because CYP3A activity in the liver and intestine was not activated to such an extent and SQV itself was not conjugated. These observations suggest that a main possible factor to explain the reducing effect on the SQV oral bioavailability during ethanol consumption is an enhanced efflux of SQV at the intestine and liver, where it is suggested that functional enhancement or excessive expression of P-glycoprotein is caused by ethanol consumption.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan. shibata@mb.kyoto-phu.ac.jp
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Shibata
authors.forename: Michiharu
authors.initials: M
authors.lastname: Kageyama
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kimura
authors.forename: Jun
authors.initials: J
authors.lastname: Tadano
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hukushima
authors.forename: Hitomi
authors.initials: H
authors.lastname: Namiki
authors.forename: Yukako
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Kanji
authors.initials: K
authors.lastname: Takada
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000428:Alcohol Drinking / Q000009:adverse effects; D000818:Animals; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D003864:Depression, Chemical; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000097:blood* / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000648:ultrastructure; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019258:Saquinavir / Q000097:blood* / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D000431:Ethanol; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D019258:Saquinavir