| Hepatobiliary disposition of 3'-azido-3'-deoxythymidine (AZT) in the rat: effect of phenobarbitone induction. | |
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MedLine Citation:
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PMID: 7996386 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Isolated liver with a recirculating perfusate was used to study 3'-azido-3'-deoxythymidine (AZT) disposition in phenobarbitone-pretreated rats at 68 microM AZT concentration in the reservoir. Clearance of AZT in the livers obtained from control animals was 0.42 +/- 0.01 (mean +/- s.d.) mL min-1/10 g liver. Over the study period of 105 min, 12.7 +/- 2.6% of the dose was excreted in bile and of this 95% was recovered as 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine (GAZT). The amount of GAZT found in the perfusate after 105 min of liver perfusion was < 1% of the AZT dose introduced into the reservoir. Phenobarbitone pretreatment of rats resulted in a 5.5-fold increase of AZT clearance. In addition, the area under the perfusate concentration-time curve (AUC0-105 min) for 3'-amino-3'-deoxythymidine (AMT) and for a catabolite of unknown structure was increased 3- and 10-fold, respectively, and the amount of AZT dose excreted in the bile was nearly doubled. Thus phenobarbitone was capable of stimulating both detoxification of AZT to GAZT and bioactivation of AZT to AMT, a catabolite known to be highly toxic to human bone marrow cells. This induction was the result of enhancement of AZT catabolism rather than its transport into the cells, since on incubation of AZT (0-250 microM) with rat isolated hepatocytes, a linear relationship between concentration and amount taken up by the cells was shown. In addition, the rate of AZT uptake was not influenced by KCN, dinitrophenol, or temperature, which is consistent with a simple diffusion of AZT through the hepatocellular membrane.(ABSTRACT TRUNCATED AT 250 WORDS) |
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Authors:
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S Bezek; M Kukan; P Bohov |
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Publication Detail:
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Type: Comparative Study; Journal Article |
Journal Detail:
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Title: The Journal of pharmacy and pharmacology Volume: 46 ISSN: 0022-3573 ISO Abbreviation: J. Pharm. Pharmacol. Publication Date: 1994 Jul |
Date Detail:
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Created Date: 1995-01-13 Completed Date: 1995-01-13 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0376363 Medline TA: J Pharm Pharmacol Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 575-80 Citation Subset: IM |
Affiliation:
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Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bile / drug effects, metabolism* Bone Marrow / drug effects Cattle Cell Survival / drug effects Cells, Cultured Chromatography, Thin Layer Dinitrophenols / toxicity Dose-Response Relationship, Drug Drug Interactions Duodenum / drug effects Glucuronosyltransferase / pharmacology Humans Liver / cytology, drug effects, metabolism* Male Phenobarbital / pharmacology* Potassium Cyanide / toxicity Rats Rats, Wistar Temperature Zidovudine / administration & dosage, analogs & derivatives*, metabolism, pharmacokinetics*, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Dinitrophenols; 117675-21-5/3'-azido-3'-deoxy-5'-O-beta-glucopyranuronosylthymidine; 151-50-8/Potassium Cyanide; 30516-87-1/Zidovudine; 50-06-6/Phenobarbital; EC 2.4.1.17/Glucuronosyltransferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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