Dose-independent pharmacokinetics of a new neuroprotective agent for ischemia-reperfusion damage, KR-31543, after intravenous and oral administration to rats: hepatic and intestinal first-pass effects.

Abstract

The purpose of this study was to report dose-independent pharmacokinetics of KR-31543, a new neuroprotective agent for ischemia-reperfusion damage, after intravenous (iv) and oral (po) administration and first-pass effects after iv, intraportal, intragastric, and intraduodenal administration in rats. After iv (10, 20, and 50 mg/kg) and oral (10, 20, and 50 mg/kg) administration, the pharmacokinetic parameters of KR-31543 were dose independent. The extent of absolute oral bioavailability (F) was 27.4% at 20 mg/kg. Considering the amount of unabsorbed KR-31543 from the gastrointestinal tract at 24 h (4.11%), the low F value could be due to the hepatic, gastric, and/or intestinal first-pass effects. After iv administration of three doses, the total body clearances were considerably slower than the reported cardiac output in rats, suggesting almost negligible first-pass effect in the heart and lung in rats. The areas under the plasma concentration-time curves from time zero to time infinity (AUCs) were not significantly different between intragastric and intraduodenal administration of KR-31543 (20 mg/kg), suggesting that the gastric first-pass effect of KR-31543 was almost negligible in rats. However, the values were significantly smaller (305 and 318 microg x min/mL) than that after intraportal administration (494 microg x min/mL), indicating a considerable intestinal first-pass effect of KR-31543 in rats; that is, approximately 40% of the oral dose. Approximately 50% of KR-31543 absorbed into the portal vein was eliminated by the liver (hepatic first-pass effect) based on iv and intraportal administration (the value, 50%, was equivalent to approximately 30% of the oral dose). The low F value of KR-31543 after oral administration of 20 mg/kg to rats was mainly due to considerable intestinal (approximately 40%) and hepatic (approximately 30%) first-pass effects.

• Authors: Mi H Lee, Soo K Bae, Eun J Kim, Yoon G Kim, Sun-O Kim, Dong H Lee, Hong Lim, Sung-E Yoo, Myung G Lee
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 92 Issue 1 Pg. 190-201 (Jan 2003) ISSN: 0022-3549 [Print] United States
• PMID: 12486695 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association

Chemical References

• Benzopyrans
• KR-31543
• Neuroprotective Agents
• Tetrazoles

Topics

• Administration, Oral
• Animals
• Benzopyrans (administration & dosage, chemistry, pharmacokinetics)
• Dose-Response Relationship, Drug
• Humans
• Infusions, Intravenous
• Intestinal Mucosa (metabolism)
• Intestines (drug effects)
• Liver (drug effects, metabolism)
• Male
• Neuroprotective Agents (administration & dosage, chemistry, pharmacokinetics)
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (drug therapy, metabolism)
• Tetrazoles (administration & dosage, chemistry, pharmacokinetics)
• Tissue Distribution (drug effects, physiology)