title: Effects of the inhibition of intestinal P-glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys.
abstract: Aliskiren is a substrate for P-glycoprotein (P-gp) and is metabolized via cytochrome P450 3A4 (CYP3A4). The aim of the present study was to assess whether P-gp influenced the pharmacokinetics of aliskiren and also if drug-drug interactions (DDIs) mediated through P-gp could be reproduced in cynomolgus monkeys. The study investigated the pharmacokinetics of aliskiren in mdr1a/1b gene-deficient (P-gp KO) and wild-type (WT) mice. The area under the plasma concentration-time curve (AUC) following the oral administration of aliskiren was 6.9-fold higher in P-gp KO mice than in WT mice, while no significant differences were observed in the AUC or total plasma clearance following the intravenous administration of aliskiren to P-gp KO mice. Then the pharmacokinetics of aliskiren were evaluated and DDIs between aliskiren and P-gp inhibitors, such as cyclosporin A (CsA) and zosuquidar, examined in cynomolgus monkeys. The AUC for aliskiren were 8.3- and 42.1-fold higher after the oral administration of aliskiren with the concomitant oral administration of zosuquidar and CsA at doses of 10 and 30 mg/kg, respectively. In contrast, the AUC after the intravenous and oral administration of aliskiren was not significantly affected by the oral administration of zosuquidar or intravenous administration of CsA, respectively. These results indicated that P-gp strictly limited the intestinal absorption of aliskiren in mice and monkeys, and also that the effects of intestinal P-gp inhibition by CsA or zosuquidar on the pharmacokinetics of aliskiren were sensitively reproduced in monkeys. In conclusion, aliskiren can be used as a sensitive substrate to evaluate intestinal P-gp inhibition in monkeys.
authors.affiliation: Discovery Screening Center, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama, Japan; Department of Clinical Pharmaceutics, School of Pharmaceutical Sciences, University of Shizuoka, Suruga, Shizuoka, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Tsukimoto
authors.forename: Rikiya
authors.initials: R
authors.lastname: Ohashi
authors.forename: Nao
authors.initials: N
authors.lastname: Torimoto
authors.forename: Yoko
authors.initials: Y
authors.lastname: Togo
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Toshio
authors.initials: T
authors.lastname: Maeda
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kagawa
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000577:Amides / Q000493:pharmacokinetics*; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005650:Fumarates / Q000493:pharmacokinetics*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011804:Quinolines / Q000494:pharmacology; D013045:Species Specificity; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000577:Amides; D000959:Antihypertensive Agents; D016572:Cyclosporine; D003986:Dibenzocycloheptenes; D005650:Fumarates; D011804:Quinolines; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C446481:aliskiren; C095179:zosuquidar trihydrochloride; C095122:multidrug resistance protein 3
keywords: aliskiren; cynomolgus monkeys; inhibition; intestine; P-gp; pharmacokinetics