title: 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.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors.forename: Mi H
authors.initials: MH
authors.lastname: Lee
authors.forename: Soo K
authors.initials: SK
authors.lastname: Bae
authors.forename: Eun J
authors.initials: EJ
authors.lastname: Kim
authors.forename: Yoon G
authors.initials: YG
authors.lastname: Kim
authors.forename: Sun-O
authors.initials: SO
authors.lastname: Kim
authors.forename: Dong H
authors.initials: DH
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Lim
authors.forename: Sung-E
authors.initials: SE
authors.lastname: Yoo
authors.forename: Myung G
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007262:Infusions, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism*; D013777:Tetrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D001578:Benzopyrans; C473251:KR-31543; D018696:Neuroprotective Agents; D013777:Tetrazoles