| Effective metabolism and long intracellular half life of the anti-hepatitis B agent adefovir in hepatic cells. | |
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MedLine Citation:
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PMID: 15450948 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Adefovir dipivoxil (ADV) is esterolytically cleaved to the 2'-deoxyadenosine monophosphate (dAMP) analog adefovir, subsequent phosphorylation leads to the formation of the anti-Hepatitis B virus (HBV) agent adefovir-DP. To better understand the mechanism of action of ADV, metabolism studies were done in Hep G2, Huh-7 and primary human hepatocytes. Separation of radiolabeled adefovir metabolites after incubation in Hep G2 cells suggested that adefovir in its mono- and di-phosphorylated forms are the only metabolites formed from adefovir. Incubation of 10 microM adefovir with hepatic cell lines and fresh monolayers of primary human hepatocytes from two donors and analysis of intracellular metabolites by liquid chromatography coupled to tandem mass spectrometry resulted in adefovir-DP levels of approximately 10 pmol/million cells. Adefovir was more efficiently phosphorylated in primary hepatocytes than cell lines with adefovir-DP accounting for 44% versus 26% of total intracellular adefovir after 24 h. Egress studies showed adefovir-DP to have a half-life of 33 +/- 3 h, 10 +/- 1 h, 48 +/- 3 h and 33 +/- 2 h in Hep G2, Huh-7, and primary hepatocytes from two separate donors, respectively. The markedly shorter half-life in Huh-7 cells was inferred to be transport dependent based on its sensitivity to the transport inhibitor MK-571. Effective phosphorylation coupled with a long intracellular half-life and small competing dATP pool sizes in primary hepatocytes forms the cellular metabolic basis for the efficacy of adefovir dipivoxil in the treatment of chronic hepatitis B. |
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Authors:
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Adrian S Ray; Jennifer E Vela; Loren Olson; Arnold Fridland |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Biochemical pharmacology Volume: 68 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2004 Nov |
Date Detail:
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Created Date: 2004-09-28 Completed Date: 2004-11-23 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1825-31 Citation Subset: IM |
Affiliation:
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Department of Drug Metabolism, Gilead Sciences, Inc., Foster City, CA 94404, USA. aray@gilead.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenine
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analogs & derivatives*,
pharmacokinetics* Animals Antiviral Agents / pharmacokinetics* Biological Transport Cells, Cultured Deoxyadenine Nucleotides / metabolism Half-Life Hepatitis B virus / drug effects Hepatocytes / metabolism* Humans Phosphonic Acids / pharmacokinetics* Phosphorylation |
| Chemical | |
Reg. No./Substance:
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0/Antiviral Agents; 0/Deoxyadenine Nucleotides; 0/Phosphonic Acids; 106941-25-7/adefovir; 1927-31-7/2'-deoxyadenosine triphosphate; 73-24-5/Adenine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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