Dose-dependent pharmacokinetics of KR-31378, a new neuroprotective agent for ischaemia-reperfusion damage in dogs.

Abstract

Dose-dependent pharmacokinetic parameters of KR-31378, a new neuroprotective agent for ischaemia-reperfusion damage, were evaluated after intravenous and oral administration of the drug at doses of 5, 10 and 25 mg/kg to male beagle dogs. After intravenous administration, the dose-normalized (based on 5 mg/kg) areas under the plasma concentration-time curve from time zero to time infinity (AUC values, 725, 1450 and 2300 micro g min/ml for 5, 10 and 25 mg/kg, respectively) were significantly different among the three dose ranges studied; the value increased more proportionally as the dose increased. This could be due to slower total body clearance (Cl) with increasing doses (6.90, 3.46 and 2.17 ml/min/kg). The slower Cl value with increasing doses may be due to saturable metabolism of KR-31378 in dogs. After oral administration, the dose-normalized (based on 5 mg/kg) AUC values (833, 1450 and 1920 micro g min/ml) at 5 mg/kg were significantly smaller than those at 10 and 25 mg/kg. Note that the AUC values were comparable (not significantly different) between intravenous and oral administration at all doses studied, indicating that the absorption of KR-31378 from the gastrointestinal tract was essentially complete and the first-pass (gastric, intestinal and/or hepatic first-pass) effects were almost negligible in dogs.

• Authors: Sun-O Kim, Sang-H Kwak, Byung H Lee, Dong-H Lee, Hong Lim, Sung-E Yoo, Hye J Chung, Myung G Lee
• Journal: Biopharmaceutics & drug disposition (Biopharm Drug Dispos) Vol. 25 Issue 3 Pg. 143-8 (Apr 2004) ISSN: 0142-2782 [Print] England
• PMID: 15083503 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2004 John Wiley & Sons, Ltd.

Chemical References

• Guanidines
• N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
• Neuroprotective Agents
• Pyrans

Topics

• Administration, Oral
• Animals
• Apoptosis (drug effects)
• Area Under Curve
• Biological Availability
• Brain Ischemia (complications)
• Dogs
• Dose-Response Relationship, Drug
• Guanidines (administration & dosage, pharmacokinetics)
• Infusions, Intravenous
• Male
• Neuroprotective Agents (administration & dosage, pharmacokinetics)
• Pyrans (administration & dosage, pharmacokinetics)
• Reperfusion Injury (drug therapy, etiology)
• Time Factors