Document 0536
 DOCN  M9440536
 TI    Comparison of a new orally potent tripeptide HIV-1 protease inhibitor
       (anti-AIDS drug) based on pharmacokinetic characteristics in rats after
       intravenous and intraduodenal administrations.
 DT    9404
 AU    Kiriyama A; Mimoto T; Kisanuki S; Kiso Y; Takada K; Department of
       Pharmaceutics and Pharmacokinetics, Kyoto; Pharmaceutical University,
       Japan.
 SO    Biopharm Drug Dispos. 1993 Nov;14(8):697-707. Unique Identifier :
       AIDSLINE MED/94137931
 AB    Recently, a series of KNI compounds such as KNI-227 and KNI-272 has been
       synthesized and shows potent and selective HIV-1 protease inhibitory
       activity in vitro. In this study, we developed an HPLC assay system for
       KNI-227 and KNI-272 in rat plasma and examined the pharmacokinetic
       characteristics in rats after both intravenous (i.v.) and intraduodenal
       (i.d.) administrations to obtain the disposition characteristics and
       bioavailabilities of these new anti-AIDS drugs. After i.v.
       administration of KNI-227, 10.0 mg kg-1, the mean terminal elimination
       half-life, t1/2 lambda zeta, was 0.808 +/- 0.161(SE) h, the total body
       clearance, CLtot, was 11.7 +/- 3.3 ml min-1 and the distribution volume
       at steady state (Vd,ss) was 1410 +/- 460 ml kg-1. On the other hand,
       after i.v. administration of KNI-272, 10.0 mg kg-1, t1/2 lambda zeta was
       2.86 +/- 0.78 h, CLtot was 15.3 +/- 1.4 ml min-1 and Vd,ss was 3440 +/-
       670 ml kg-1. In the case of the i.d. administration of drugs, the mean
       peak plasma concentrations, Cmax, of KNI-227 and KNI-272 were 0.374 +/-
       0.110 microgram ml-1 and 0.900 +/- 0.093 micrograms ml-1, respectively.
       The bioavailabilities (BA) of KNI-227 and KNI-272 to infinity,
       BA(0-infinity), were 5.90% and 42.3%, respectively. As compared with the
       lead compound, KNI-174, the BA of KNI-272 was improved about 10 times.
       Although the anti-AIDS virus activity of these two drugs has not been
       investigated in vivo, KNI-272 is expected to be a better candidate for
       oral anti-AIDS therapies.
 DE    Animal  Biological Availability  Comparative Study  Duodenum  Half-Life
       HIV Protease Inhibitors/*PHARMACOKINETICS  Injections, Intravenous
       Intubation, Gastrointestinal  Male  Oligopeptides/*PHARMACOKINETICS
       Rats  Rats, Wistar  JOURNAL ARTICLE

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