| Physiologic and metabolic influences on enterohepatic recirculation: simulations based upon the disposition of valproic acid in the rat. | |
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MedLine Citation:
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PMID: 2013839 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The potential influence of alterations in several physiologic processes (hepatocellular egress, biliary excretion, gastrointestinal transit) and biotransformation steps (oxidative metabolism, glucuronidation) on the disposition of agents subject to significant enterohepatic recirculation (ER) via the glucuronide conjugate was examined in a series of simulation experiments. The model of ER developed was based upon the disposition of valproic acid (VPA) and valproate glucuronide (VPA-G) in the rat. The systemic disposition of VPA was simulated following changes in several processes contributing to (or competing with) ER: hepatic oxidative metabolism, hepatic glucuronidation, sinusoidal egress of glucuronide conjugate, canalicular egress of glucuronide conjugate, and gastrointestinal transit. Changes in the formation clearance of VPA-G resulted in a less than proportional change in systemic clearance of VPA, whereas changes in oxidative metabolism led to a greater than proportional change in systemic clearance. Furthermore, alterations in hepatocellular egress of VPA-G affected the disposition of the parent compound, suggesting that drug interactions or disease state effects on metabolite transport may be misinterpreted as effects at the level of metabolite formation. Analytical methods are proposed to recover the intrinsic kinetic parameters (formation clearances of metabolites, renal clearance of parent, volume of distribution) in the presence of ER from the systemic disposition of the parent alone. |
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Authors:
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G M Pollack; K L Brouwer |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of pharmacokinetics and biopharmaceutics Volume: 19 ISSN: 0090-466X ISO Abbreviation: J Pharmacokinet Biopharm Publication Date: 1991 Apr |
Date Detail:
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Created Date: 1991-05-13 Completed Date: 1991-05-13 Revised Date: 2003-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0357115 Medline TA: J Pharmacokinet Biopharm Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 189-225 Citation Subset: IM |
Affiliation:
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Division of Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bile / metabolism Enterohepatic Circulation* Glucuronates / metabolism Male Models, Biological Rats Rats, Inbred Strains Valproic Acid / pharmacokinetics* |
| Chemical | |
Reg. No./Substance:
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0/Glucuronates; 99-66-1/Valproic Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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