Dose-dependent pharmacokinetics of a new Na+/H+ exchanger inhibitor KR-33028 in rats

✍ Scribed by Young Hoon Kim; Sun Dong Yoo; You Sun Kim; Kyung Hee Lee; Hye Suk Lee

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 126 KB
• Volume: 28
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.571

✦ Synopsis

Abstract

The dose‐dependency of the pharmacokinetics of a new Na^+^/H^+^ exchanger inhibitor, KR‐33028 was evaluated in rats after intravenous and oral administration. After intravenous administration of KR‐33028 (1, 5, 10 and 20mg/kg doses), the systemic clearance (Cl) was reduced and AUC was nonlinearly increased as a function of dose. The volume of distribution (V~ss~), however, remained unchanged as the dose was increased, which was consistent with unaltered plasma protein binding in vitro (unbound fraction = 0.09–0.12). Upon oral administration (2, 10 and 20mg/kg doses), KR‐33028 was rapidly absorbed, and this was consistent with high Caco‐2 P~app~ values found in vitro. There were nonlinear increases in AUC and C~max~, and the absolute oral bioavailability (F) was significantly increased as the dose was increased (F = 23.3%, 40.7% and 78.2% for 2, 10 and 20mg/kg doses, respectively). The extent of urinary excretion was low for both intravenous (0.5–0.7%) and oral (0.2–0.8%) doses. The reduced systemic clearance and increased oral bioavailability at high doses appears to be due to a saturable first‐pass metabolism. Copyright © 2007 John Wiley & Sons, Ltd.