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 sele ctive HIV-1 protease inhibitor, were evaluated in rats after intraveno us (IV) administration. The effect of dose on KNI-272 plasma kinetics, and the urinary and biliary elimination kinetics of KNI-272, were exa mined. After IV administration of 10.0 mg kg(-1) KNI-272, the mean ter minal elimination half-life, t(1/2 lambda z), 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,V-ss, was 3790 +/- 280 m L kg(-1). On the other hand, after 1.0 mg kg(-1) IV administration, t( 1/2 lambda z) was 3.04 +/- 0.11 h, CL(tot) was 15.9 +/- 0.2 mL min(-1) , and V-d,V-ss was 6950 +/- 600 mL kg(-1). The PK parameters of KNI-27 2 after IV administration showed that the disposition of KNI-272 in th e 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 mu g mL(-1), 0.888 +/- 0.008 mu g mL(-1), and 0.470 +/- 0.55 mu g mL(-1), respectively. The percentages of the dose excreted into t he 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 (CL(R)) an d the biliary clearance (CL(B)) were calculated to be 0.191 and 0.256m L 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 CL(tot) values, the urinary and biliary excretion of KNI-272 are minor disposi tion routes.