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 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 microg min/mL) was significantly greater than that at 10 (569 microg min/ml) and 20 (660 microg 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 microg min/mL) was significantly greater than that at 10 (572 microg min/mL) and 20 (786 microg 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.
Kim
H J
HJ
College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Kim
S H
SH
Kim
S O
SO
Lee
D H
DH
Lim
H
H
Yoo
S E
SE
Lee
M G
MG
D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000493:pharmacokinetics*; D008297:Male; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011714:Pyrans / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy*
D006146:Guanidines; C438686:N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine; D018696:Neuroprotective Agents; D011714:Pyrans