Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV-1 protease inhibitor, KNI-272, in rats after intravenous administration.
The pharmacokinetic (PK) characteristics of KNI-272, a potent and selective HIV-1 protease inhibitor, were evaluated in rats after intravenous (IV) administration. The effect of dose on KNI-272 plasma kinetics, and the urinary and biliary elimination kinetics of KNI-272, were examined. After IV administration of 10.0 mg kg-1 KNI-272, the mean terminal elimination half-life, t1/2 lambda zeta, was 3.49 +/- 0.19 (SE) h, the total plasma clearance, CLtot, was 15.1 +/- 1.2 mL min-1 and the distribution volume at steady state, Vd,ss, was 3790 +/- 280 mL kg-1. On the other hand, after 1.0 mg kg-1 IV administration, t1/2 lambda zeta was 3.04 +/- 0.11 h, CLtot was 15.9 +/- 0.2 mL min-1, and Vd,ss was 6950 +/- 600 mL kg-1. The PK parameters of KNI-272 after IV administration showed that the disposition of KNI-272 in the rat plasma is linear within the dose range from 1.0 to 10.0 mg kg-1. Using an equilibrium dialysis method, the plasma binding of KNI-272 was measured in vitro. The free fractions were 17.7 +/- 0.6%, 12.1 +/- 1.5%, and 13.8 +/- 1.4% at the total concentration ranges of 9.898 +/- 0.097 microgram mL-1, 0.888 +/- 0.008 microgram mL-1, and 0.470 +/- 0.55 microgram mL-1, respectively. The percentages of the dose excreted into the urine and bile as the unchanged form were 1.20 +/- 1.06% and 1.61 +/- 0.32% at 1.0 mg kg-1 dose, and 0.164 +/- 0.083% and 1.42 +/- 0.26% at 10.0 mg kg-1 dose, respectively. The renal clearance (CLR) and the biliary clearance (CLB) were calculated to be 0.191 and 0.256 mL min-1 for 1.0 mg kg-1, and 0.0248 and 0.215 mL min-1 for 10.0 mg kg-1, respectively. When comparing these values with the CLtot values, the urinary and biliary excretion of KNI-272 are minor disposition routes.
Kiriyama
A
A
Department of Pharmaceutics and Pharmacokinetics, Kyoto Pharmaceutical University, Japan.
Fujita
K
K
Takemura
S
S
Kuramoto
H
H
Kiso
Y
Y
Takada
K
K
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D003956:Dialysis; D004305:Dose-Response Relationship, Drug; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006207:Half-Life; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D008962:Models, Theoretical; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012015:Reference Standards; D015203:Reproducibility of Results
D000998:Antiviral Agents; D001798:Blood Proteins; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; C077822:kynostatin 272