Bioavailability of the amino acid-attached prodrug as a new anti-HIV agent in rats

The primary objective of this study was to compare the pharmacokinetics of a new anti-human immunodeficiency virus agent 1-(2-amino-pyridin-4-ylmethyl)-6-(3,5-dimethyl-benzoyl)-5-isopropyl-1H-pyrimidine-2,4-dione (VP-0502) with its amino acid prodrug alanine amide of VP-0502 (VP-0502AL), following intravenous and oral administrations to rats. The plasma concentrations of both analytes were analyzed via high-performance liquid chromatography coupled with photodiode-array detection (HPLC-DAD). When VP-0502 was intravenously administered at 20 mg/kg, the analyte appeared in low levels with an AUC of 0.3 µg · h/ml, and C(0) of 0.2 µg/ml in plasma. However, both the prodrug VP-0502AL and its metabolite VP-0502 appeared at comparatively higher levels following intravenous injection of VP-0502AL at the same dose. VP-0502AL's pharmacokinetic parameters were V(d): 4.6 l/kg; AUC: 3 µg · h/ml; t(1/2): 0.5 h; C(0): 6 µg/ml; CL(tot): 7 l/h/kg; and MRT: 0.6 h. Following oral administration of VP-0502 (100 mg/kg), it was not detectable in plasma (<50 ng/ml), while after the oral administration of VP-0502AL, VP-0502 was quantitatively detected as an active metabolite for the first 7 h, with a maximum plasma concentration (C(max)) of 0.8 µg/ml, and an area under the concentration-time curve (AUC) of 2 µg · h/ml. The oral pharmaco-kinetic parameters of VP-0502AL were calculated to be: maximum concentration time (t(max)) 2.7 h; C(max) 0.2 µg/ml; elimination half-life (t(1/2)): 0.8 h; and AUC 0.5 µg · h/ml. Overall the findings indicate that VP-0502AL has a favorable pharmacokinetic profile as a prodrug with rapid transformation into the active metabolite, and that the attachment of the amino acid alanine to VP-0502 is an effective approach to improve its oral bioavailability. VP-0502AL is predicted to become a new highly bioavailable anti-AIDS drug candidate and/or lead compound.