Dose-dependent pharmacokinetics of a new neuroprotective agent for ischemia-reperfusion damage, KR-31378, in rats

The dose-dependent pharmacokinetic parameters of a new neuroprotective agen t for ischemia-reperfusion damage, KR-31378, were evaluated after intraveno us and oral administration, 10, 20, and 50 mg/kg, to rats. After intravenou s administration of 50 mg/kg, the dose-normalized 10 mg/kg) AUC (994 mug mi n/mL) was significantly greater than that at 10 (569 mug min/ml) and 20 (66 0 mug min/mL) mg/kg. This could be due to slower clearance (Cl) with increa sing dosage (18.5, 14.6, and 10.2 mL/min/kg for 10, 20, and 50 mg/kg, respe ctively). The slower Cl with increasing dosage could be due to saturable me tabolism of KR-31378 in rats and this could be supported by significantly s lower 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 mug min/mL was significantly greater than that at 10 (572 mug min/mL) and 20 (786 mug min/mL) mg/kg. Not e that the AUCs were comparable (not significantly different) between intra venous and oral administration at each dosage, indicating that the absorpti on from gastrointestinal tract was almost complete and the first-pass (gast ric, intestinal, and hepatic) effect was not considerable after oral admini stration to rats. Copyright (C) 2000 John Wiley & Sons, Ltd.