Abstract
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) PMEA, 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 of PMEA per kg. Plasma samples were obtained over the course of 12 hr and concentrations of PMEA were determined by fluorescence derivatization and analysis by HPLC. Concentrations of PMEA observed in plasma following 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) PMEA were 38.2%, 2.46%, and 40.1%, respectively. PMEA was the only metabolite formed after oral administration of bis-POM PMEA. Three metabolites were detected after oral administration of either bis-(phenyl) PMEA or bis-(o-ethoxyphenyl) PMEA to rats: PMEA, the corresponding monoester, and 2-adenylacetic acid. The major metabolite of bis-(phenyl) PMEA was 2-adenylacetic acid following oral administration. 2-Adenylacetic acid appears to have been formed from the intact prodrugs by a P450 mediated oxidation of the ethyl side chain.
Footnotes
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Send reprint requests to: Dr. Jeng-Pyng Shaw, Gilead Sciences, Inc., 353 Lakeside Drive, Foster City, CA 94404.
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↵1 J.-P. Shaw, D. Burman, R. J. Jones, M. N. Arimilli, M. S. Louie, M. Lee, J. A. Kennedy, K.-Y. Lin, W. A. Lee, and K. C. Cundy: Application of in vitro screens to the selection of oral prodrugs of PMEA. Submitted for publication.
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↵2 J.-P. Shaw and K. C. Cundy, unpublished results.
- Received September 6, 1996.
- Accepted December 6, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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