title: Dose-independent pharmacokinetics of a new reversible proton pump inhibitor, KR-60436, after intravenous and oral administration to rats: gastrointestinal first-pass effect.
abstract: Dose-independent pharmacokinetic parameters of KR-60436, a new proton pump inhibitor, were evaluated after intravenous (i.v.; 5, 10, and 20 mg/kg) and oral (20, 50, and 100 mg/kg) administration to rats. The hepatic, gastric, and intestinal first-pass effects were also measured after iv, intraportal (i.p.), intragastric (i.g.), and intraduodenal (id) administrations to rats of a dose of 20 mg/kg. The areas under the plasma concentration-time curve from time to zero to time infinity (AUCs) were independent of iv and oral dose ranges studied; the dose-normalized AUCs were 83.0-104 microg. min/mL (based on 5 mg/kg) and 78.4-96.8 microg. min/mL (based on 20 mg/kg) for iv and oral administration, respectively. After an oral administration at a dose of 20 mg/kg, approximately 3% of the oral dose was not absorbed, and the extent of absolute oral bioavaliability (F) was estimated to be 18.8%. The AUCs of KR-60436 after i.g. and i.d. administration at a dose of 20 mg/kg were significantly smaller (82.4 and 57.5% decrease, respectively) than that after an i.p. administration at a dose of 20 mg/kg, suggesting that gastrointestinal first-pass effect of KR-60436 was approximately 80% of oral dose in rats (the gastric first-pass effect was approximately 25%). After an i.p. administration at a dose of 20 mg/kg, the AUC was 77.6% of an iv administration, suggesting that hepatic first-pass effect was approximately 22% of KR-60436 absorbed into the portal vein. Note that the value of 22% was equivalent to approximately 4% of the oral dose. Because only 17% of oral dose was absorbed into the portal vein, the low F of KR-60436 in rats was mainly due to considerable gastrointestinal first-pass effect, which was approximately 80% (the gastric first-pass effect was approximately 25%) of oral dose.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Yu
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Bae
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Kim
authors.forename: Yoon Gyoon
authors.initials: YG
authors.lastname: Kim
authors.forename: Sun-Ok
authors.initials: SO
authors.lastname: Kim
authors.forename: Dong Ha
authors.initials: DH
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Lim
authors.forename: Myung Gull
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D054328:Proton Pump Inhibitors; D017494:Proton Pumps / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D011804:Quinolines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: C439392:1-(2-methyl-4-methoxyphenyl)-4-((2-hydroxyethyl)amino)-6-trifluoromethoxy-2,3-dihydropyrrolo(3,2-c)quinoline; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; D011758:Pyrroles; D011804:Quinolines