Dose-independent pharmacokinetics of a new reversible proton pump inhibitor, KR-60436, after intravenous and oral administration to rats: Gastrointestinal first-pass effect

Dose-independent pharmacokinetic parameters of KR-60436, anew proton pump inhibitor, were evaluated after intravenous (iv; 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 (ip), intragastric (ig), 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 mug (.) min/mL (based on 5 mg/kg) and 78.4-96.8 mug (.) min/mL (based on 20 mg/kg) for iv and oral administration, respectively. After an oral administration at a dose of 20 mg/kg, similar to3% 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 ig and id administration at a dose of 20 mg/kg were significantly smaller (82.4 and 57.5% decrease, respectively) than that after an ip, administration at a dose of 20 mg/kg, suggesting that gastrointestinal first-pass effect-of KR-60436 was similar to80% of oral dose in rats (the gastric first-pass effect was similar to25%). After an ip administration at a dose of 20 mg/kg, the AUC was 77.6% of an iv administration, suggesting that hepatic first-pass effect was similar to22% of KR-60436 absorbed into the portal vein. Note that the value of 22% was equivalent to similar to4% 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 similar to80% (the gastric first-pass effect was similar to25%) of oral dose. (C) 2003 Wiley-Liss, Inc. and the American Pharmacists Association.