Linked Life Data

15450948

Source:http://linkedlifedata.com/resource/pubmed/id/15450948

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2004-9-28
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
68
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1825-31
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Effective metabolism and long intracellular half life of the anti-hepatitis B agent adefovir in hepatic cells.
pubmed:affiliation
Department of Drug Metabolism, Gilead Sciences, Inc., Foster City, CA 94404, USA. aray@gilead.com
pubmed:publicationType
Journal Article