Metabolism, Pharmacokinetics, Tissue Distribution, and Stability Studies of the Prodrug Analog of an Anti-Hepatitis B Virus Dinucleoside Phosphorothioate
| Autor: | John Coughlin, Rajendra K. Pandey, Seetharamaiyer Padmanabhan, Radhakrishnan P. Iyer, Jon C. Mirsalis, Carol E. Green, Judith Marquis, Kathleen O’Loughlin |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Hepatitis B virus Metabolite Administration Oral Phosphorothioate Oligonucleotides Pharmaceutical Science In Vitro Techniques Pharmacology Antiviral Agents Models Biological Mass Spectrometry Rats Sprague-Dawley chemistry.chemical_compound Drug Stability Pharmacokinetics Animals Humans Prodrugs Tissue Distribution Biotransformation Chromatography High Pressure Liquid Gastric Juice Intestinal Secretions Molecular Structure Stereoisomerism Articles Metabolism Prodrug Rats chemistry S9 fraction Drug Design Injections Intravenous Microsomes Liver Microsome Female Nucleoside |
| Zdroj: | Drug Metabolism and Disposition. 40:970-981 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.111.044446 |
| Popis: | The alkoxycarbonyloxy dinucleotide prodrug R(p), S(p)-2 is an orally bioavailable anti-hepatitis B virus agent. The compound is efficiently metabolized to the active dinucleoside phosphorothioate R(p), S(p)-1 by human liver microsomes and S9 fraction without cytochrome P450-mediated oxidation or conjugation. The conversion of R(p), S(p)-2 to R(p), S(p)-1 appears to be mediated by liver esterases, occurs in a stereospecific manner, and is consistent with our earlier reported studies of serum-mediated hydrolytic conversion of R(p), S(p)-2 to R(p), S(p)-1. However, further metabolism of R(p), S(p)-1 does not occur. The presence of a minor metabolite, the desulfurized product 10 was noted. The prodrug R(p), S(p)-2 was quite stable in simulated gastric fluid, whereas the active R(p), S(p)-1 had a half-life of |
| Databáze: | OpenAIRE |
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