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Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV‐1 protease inhibitor, KNI‐272, in rats after intravenous administration
Author(s) -
Kiriyama A.,
Fujita K.,
Takemura S.,
Kuramoto H.,
Kiso Y.,
Takada K.
Publication year - 1994
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510150709
Subject(s) - pharmacokinetics , chemistry , volume of distribution , pharmacology , oral administration , urine , excretion , enzyme inhibitor , in vitro , medicine , biochemistry
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, t 1/2λz , was 3.49 ± 0.19 (SE) h, the total plasma clearance, CL tot , was 15.1 ± 1.2 mL min −1 and the distribution volume at steady state, V d,ss , was 3790±280 mL kg −1 . On the other hand, after 1.0mg kg −1 IV administration, t d,ss , was 3.04±0.11 h, CL tot was 15.9±0.2mL min −1 , and V d,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 10.0mg 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 μg mL −1 , 0.888 ± 0.008 μg mL −1 , and 0.470±0.55 μg 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 1.0mg kg −1 dose, and 0.164 ± 0.083% and 1.42 ± 0.26% at 10.0 mg kg −1 dose, respectively. The renal clearance (CL R ) and the biliary clearance (CL B ) were calculated to be 0.191 and 0.256mL min −1 for 1.0mg kg −1 , and 0.0248 and 0.215 mL min −1 for 10.0 mg kg −1 , respectively. When comparing these values with the CL tot values, the urinary and biliary excretion of KNI‐272 are minor disposition routes.