PHARMACOKINETICS AND METABOLISM OF SELECTED PRODRUGS OF PMEA IN RATS

The oral bioavailability of PMEA (9-[2-(phosphonomethoxy)ethyl]adenine ; adefovir) has been determined in rats from three bis-ester prodrugs of PMEA: bis-(pivaloyloxymethyl) PMEA (bis-POM PMEA), bis-(phenyl) PME A, and bis-(o-ethoxyphenyl) PMEA, The prodrugs were each administered to 9 male rats as solutions in PEG 400 at a dose of 10 mg-equivalent o f PMEA per kg. Plasma samples were obtained over the course of 12 hr a nd concentrations of PMEA were determined by fluorescence derivatizati on and analysis by HPLC. Concentrations of PMEA observed in plasma fol lowing oral administration of PMEA prodrugs were compared with levels observed for intravenous PMEA. The observed oral bioavailabilities of PMEA from bis-POM PMEA, bis-(phenyl) PMEA, and bis-(o-ethoxyphenyl) PM EA were 38.2%, 2.46%, and 40.1%, respectively. PMEA was the only metab olite formed after oral administration of bis-POM PMEA, Three metaboli tes were detected after oral administration of either bis-(phenyl) PME A or bis-(o-ethoxyphenyl) PMEA to rats: PMEA, the corresponding monoes ter, and 2-adenylacetic acid. The major metabolite of bis-(phenyl) PME A was 2-adenylacetic acid following oral administration, 2-Adenylaceti c acid appears to have been formed from the intact prodrugs by a P450 mediated oxidation of the ethyl side chain.