Document 0706
 DOCN  M9550706
 TI    Plasma pharmacokinetics and urinary and biliary excretion of a new
       potent tripeptide HIV-1 protease inhibitor, KNI-272, in rats after
       intravenous administration.
 DT    9505
 AU    Kiriyama A; Fujita K; Takemura S; Kuramoto H; Kiso Y; Takada K;
       Department of Pharmaceutics and Pharmacokinetics, Kyoto; Pharmaceutical
       University, Japan.
 SO    Biopharm Drug Dispos. 1994 Oct;15(7):617-26. Unique Identifier :
       AIDSLINE MED/95151988
 AB    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.
 DE    Animal  Antiviral Agents/ADMINISTRATION &
       DOSAGE/BLOOD/*PHARMACOKINETICS/  URINE  Bile/METABOLISM  Blood
       Proteins/METABOLISM  Calibration  Chromatography, High Pressure Liquid
       Dialysis  Dose-Response Relationship, Drug  Half-Life  HIV Protease
       Inhibitors/ADMINISTRATION & DOSAGE/BLOOD/  *PHARMACOKINETICS/URINE  In
       Vitro  Injections, Intravenous  Male  Models, Theoretical
       Oligopeptides/ADMINISTRATION & DOSAGE/BLOOD/*PHARMACOKINETICS/  URINE
       Protein Binding  Rats  Rats, Wistar  Reference Standards
       Reproducibility of Results  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).