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

ABSTRACT

The primary objective of this study was to compare thepharmacokinetics of a new anti-human immunodeficiencyvirus 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 administrationsto rats. The plasma concentrations of both analytes wereanalyzed via high-performance liquid chromatographycoupled with photodiode-array detection (HPLC-DAD).When VP-0502 was intravenously administered at 20mg/kg, the analyte appeared in low levels with an AUC of 0.3microg.h/ml, and C0 of 0.2microg/ml in plasma. However, boththe prodrug VP-0502AL and its metabolite VP-0502 appearedat comparatively higher levels following intravenousinjection of VP-0502AL at the same dose. VP-0502AL'spharmacokinetic parameters were Vd 4.6 l/kg; AUC3microg.h/ml; t1/2 0.5h; C0 6microg/ml; CLtot 7l/h/kg; andMRT 0.6h. Following oral administration of VP-0502(100mg/kg), it was not detectable in plasma (<50ng/ml),while after the oral administration of VP-0502AL, VP-0502 was quantitatively detected as an active metabolite forthe first 7h, with a maximum plasma concentration(Cmax) of 0.8microg/ml, and an area under the concentration-time curve (AUC) of 2microg.h/ml. The oral pharmacokineticparameters of VP-0502AL were calculated to be maximumconcentration time (tmax) 2.7h; Cmax 0.2microg/ml; eliminationhalf-life (t1/2) 0.8h; and AUC 0.5microg.h/ml. Overall thefindings indicate that VP-0502AL has a favorable pharmaco-kinetic profile as a prodrug with rapid transformationinto the active metabolite, and that the attachment of theamino acid alanine to VP-0502 is an effective approach toimprove its oral bioavailability. VP-0502AL is predictedto become a new highly bioavailable anti-AIDS drugcandidate and/or lead compound.