| Disposition of cosalane, a novel anti-HIV agent, in isolated perfused rat livers. | |
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MedLine Citation:
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PMID: 10421624 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cosalane is a potent inhibitor of HIV replication with a broad range of activity. In this study, the hepatic disposition of cosalane was investigated with a noncirculating isolated perfused rat liver technique. When 6 microM cosalane was infused into livers from untreated rats, the drug was highly extracted by the liver (only 2. 5% of influent cosalane concentration appeared in the effluent perfusate). Pretreatment of rats with various inducers of cytochrome P-450 before perfusion neither altered the effluent cosalane concentration nor resulted in the appearance of detectable metabolites in the effluent perfusate or liver homogenates. Hepatic uptake of cosalane was negligible when the drug was infused in the presence of BSA, and infusion of albumin after cosalane resulted in a significant displacement of the drug into the effluent perfusate. Furthermore, permeabilization of perfused livers with digitonin significantly diminished effluent cosalane concentration while enhancing cosalane uptake by the liver. Based on our data, it appears that a significant proportion of cosalane does not penetrate the hepatocyte membrane and may accumulate in the lipid bilayer of the cell membrane. This finding supports the proposed mechanism explaining the antiviral effect of cosalane which stipulates that this compound appears to imbed perpendicularly in the lipid bilayer of the cell membrane and the viral envelope. Also, cosalane does not seem to be metabolized by the liver as evidenced by the lack of detectable metabolites in the effluent perfusate, liver homogenates, and liver microsomal incubations. |
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Authors:
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C Udata; A K Mitra; M Z Badr |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 27 ISSN: 0090-9556 ISO Abbreviation: Drug Metab. Dispos. Publication Date: 1999 Aug |
Date Detail:
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Created Date: 1999-10-01 Completed Date: 1999-10-01 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 947-50 Citation Subset: IM; X |
Affiliation:
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Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 64108-2792, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-HIV Agents / pharmacokinetics* Aurintricarboxylic Acid / analogs & derivatives*, pharmacokinetics Chromatography, High Pressure Liquid Enzyme Induction / drug effects L-Lactate Dehydrogenase / biosynthesis, metabolism Liver / cytology, enzymology, metabolism* Male Protein Binding Rats Rats, Sprague-Dawley |
| Grant Support | |
ID/Acronym/Agency:
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AI-36624/AI/NIAID NIH HHS; CA/OD 74383/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-HIV Agents; 154212-56-3/cosalane; 4431-00-9/Aurintricarboxylic Acid; EC 1.1.1.27/L-Lactate Dehydrogenase |
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