Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV-1 protease inhibitor, KNI-272, in rats after intravenous administration

✍ Scribed by A. Kiriyama; K. Fujita; S. Takemura; H. Kuramoto; Y. Kiso; K. Takada

• Publisher: John Wiley and Sons
• Year: 1994
• Tongue: English
• Weight: 555 KB
• Volume: 15
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.2510150709

✦ Synopsis

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 10-0mg kg-' KNI-272, the mean terminal elimination half-life, t1,2k, was 3-49+0* 19 (SE) h, the total plasma clearance, CL,,,, was 15-1 ? 1-2 mL min-1 and the distribution volume at steady state, V,,,, was 3790k280mL kg-'. On the other hand, after 1 .O mg kg-' IV administration, t,,,, was 3-04+0-11 h, CL,, was 15.9f0.2mLmin-', and Vd,, was 6950f600mL kg-'. 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-I. Using an equilibrium dialysis method, the plasma binding of KNI-272 was measured in vitro. The freefractionswere 17-7+0-6%, 12-1+1.5%, and 13~8+1*4%atthetotalconcentration ranges of 9 -898 + 0.097 pg mL -0.888 k 0.008 pg mL-', and 0 -470 f 0.55 pg mL-I , respectively. The percentages of the dose excreted into the urine and bile as the unchanged formwere 1.20k1.06%and 1.61+0-32%at 1~0mgkg-1dose,and0~164+0-083% and 1-42+0.26% at 10-0mg kg-' dose, respectively. The renal clearance (CLR) and the biliary clearance (CL,) were calculated to be 0.191 and 0-256mLmin-' for 1.0 mg kg-I, and 0.0248 and 0-215 mL min-I for 10.0mg kg-', respectively. When comparing these values with the CL,, values, the urinary and biliary excretion of KNI-272 are minor disposition routes.