Abstract
The dose‐dependent pharmacokinetic parameters of a new neuroprotective agent for ischemia‐reperfusion damage, KR‐31378, were evaluated after intravenous and oral administration, 10, 20, and 50 mg/kg, to rats. After intravenous administration of 50 mg/kg, the dose‐normalized (10 mg/kg) AUC (994 µg min/mL) was significantly greater than that at 10 (569 µg min/ml) and 20 (660 µg min/mL) mg/kg. This could be due to slower clearance (Cl) with increasing dosage (18.5, 14.6, and 10.2 mL/min/kg for 10, 20, and 50 mg/kg, respectively). The slower Cl with increasing dosage could be due to saturable metabolism of KR‐31378 in rats and this could be supported by significantly slower Cl~nr~ and significantly greater 24‐h urinary excretion of the drug at 50 mg/kg than those at 10 and 20 mg/kg. After oral administration of 50 mg/kg, the dose‐normalized (10 mg/kg) AUC (1160 µg min/mL) was significantly greater than that at 10 (572 µg min/mL) and 20 (786 µg min/mL) mg/kg. Note that the AUCs were comparable (not significantly different) between intravenous and oral administration at each dosage, indicating that the absorption from gastrointestinal tract was almost complete and the first‐pass (gastric, intestinal, and hepatic) effect was not considerable after oral administration to rats. Copyright © 2000 John Wiley & Sons, Ltd.