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

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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 (Vss), 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 Papp values found in vitro. There were nonlinear increases in AUC and Cmax, 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.

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