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

✍ Scribed by A. Kiriyama; T. Mimoto; S. Kisanuki; Y. Kiso; K. Takada

• Publisher: John Wiley and Sons
• Year: 1993
• Tongue: English
• Weight: 549 KB
• Volume: 14
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.2510140806

✦ Synopsis

Abstract

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, 10.0mg kg^−1^, the mean terminal elimination half‐life, t~1/2λ__z__~, was 0.808±0.161(SE)h, the total body clearance, CL~tot~, was 11.7±3.3 ml min^−1^ and the distribution volume at steady state (V~d,ss~) was 1410.460 ml kg^−1^. On the other hand, after i.v. administration of KNI‐272, 10.0mg kg^−1^, t~1/2λ__z__~ was 2.86±0.78 h, CL~tot~ was 15.3±1.4 ml min^−1^ and V~d,ss~ was 3440.670 ml kg^−1^. In the case of the i.d. administration of drugs, the mean peak plasma concentrations, C~max~, of KNI‐227 and KNI‐272 were 0.374±0.110μg ml^−1^ and 0.900±0.093 μg ml^−1^, respectively. The bioavailabilities (BA) of KNI‐227 and KNI‐272 to infinity, BA^(0‐∞)^, 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.