Pharmacokinetic study of a tripeptide HIV-1 protease inhibitor, KNI-174, in rats after intravenous and intraduodenal administrations

Recently, as a new type of anti‐AIDS drug, an HIV‐1 protease inhibitor, KNI‐174, has been synthesized; it shows a potent and selective HIV‐1 protease inhibitory activity in vitro. In this study, we developed an HPLC assay system for KNI‐174 in rat plasma and examined the pharmacokinetics of KNI‐174 in rats using this assay method after both intravenous (i.v.) and intraduodenal (i.d.) administrations to obtain the disposition characteristics and bioavailability of this new anti‐AIDS drug. This HPLC assay method is specific to KNI‐174 and the standard curve was linear from 0.02 to 30 μg ml−1 plasma. After i.v. administration, 10.0 mg kg−1, KNI‐174 disappeared from the rats' plasma in a three‐exponential decay. The mean terminal elimination half‐life, t1/2ÀZ, was 3.97 ± 0.19 (S.E.)h, the total body clearance, CLtot, was 9.53 ± 1.08 ml min−1 and the distribution volume at steady state, Vd, ss′ was 7070 ± 960 ml kg−1. In the case of the i.d. administration, 10.0 mg kg−1, the mean peak plasma concentration, Cmax, and the peak time, tmax, were 0.196 ± 0.076 μg ml−1 and 0.444 ± 0.193 h, respectively. The bioavailability of KNI‐174 till infinity, BA(0‐infinity), was 5.37 per cent. Because the IC50 of KNI‐174 against HIV‐1 in PHA‐PBM was 138 ng ml−1, the time needed for maintaining the concentrations above IC50 after a single i.d. administration of KNI‐174 is estimated to be 0.350 ± 0.184 h.