title: 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.
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, 10.0 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.
authors.affiliation: Department of Pharmaceutics and Pharmacokinetics, Kyoto Pharmaceutical University, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kiriyama
authors.forename: T
authors.initials: T
authors.lastname: Mimoto
authors.forename: S
authors.initials: S
authors.lastname: Kisanuki
authors.forename: Y
authors.initials: Y
authors.lastname: Kiso
authors.forename: K
authors.initials: K
authors.lastname: Takada
mesh_terms: D000818:Animals; D001682:Biological Availability; D004386:Duodenum; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006207:Half-Life; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; C077823:kynostatin 227; C077822:kynostatin 272