title: Dose-dependent pharmacokinetics of a new Na+/H+ exchanger inhibitor KR-33028 in rats.
abstract: The dose-dependency of the pharmacokinetics of a new Na(+)/H(+) exchanger inhibitor, KR-33028 was evaluated in rats after intravenous and oral administration. After intravenous administration of KR-33028 (1, 5, 10 and 20mg/kg doses), the systemic clearance (Cl) was reduced and AUC was nonlinearly increased as a function of dose. The volume of distribution (V(ss)), however, remained unchanged as the dose was increased, which was consistent with unaltered plasma protein binding in vitro (unbound fraction = 0.09-0.12). Upon oral administration (2, 10 and 20mg/kg doses), KR-33028 was rapidly absorbed, and this was consistent with high Caco-2 P(app) values found in vitro. There were nonlinear increases in AUC and C(max), and the absolute oral bioavailability (F) was significantly increased as the dose was increased (F = 23.3%, 40.7% and 78.2% for 2, 10 and 20mg/kg doses, respectively). The extent of urinary excretion was low for both intravenous (0.5-0.7%) and oral (0.2-0.8%) doses. The reduced systemic clearance and increased oral bioavailability at high doses appears to be due to a saturable first-pass metabolism.
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Sun Dong
authors.initials: SD
authors.lastname: Yoo
authors.forename: You Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Lee
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000493:pharmacokinetics*