| Kinetics of valproic acid glucuronidation: evidence for in vivo autoactivation. | |
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MedLine Citation:
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PMID: 17496206 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Sigmoidal or autoactivation kinetics has been observed in vitro for both cytochrome P450- and UDP-glucuronosyltransferase-catalyzed enzymatic reactions. However, the in vivo relevance of sigmoidal kinetics has never been clearly demonstrated. In the current study we investigate the kinetics of valproic acid glucuronide (VPAG) formation both in vivo in adult sheep and in vitro in sheep liver microsomes (pool of 10). After a 100 mg/kg i.v. bolus dose of valproic acid (VPA) to adult sheep (n = 5), the majority of the dose was recovered in urine as VPAG (approximately 79%). Eadie-Hofstee plots of the VPAG formation rate (calculated from urinary excretion rate data for VPAG) were characteristic of autoactivation kinetics and provided estimates of the apparent maximum velocity of an enzymatic reaction (V(max)(app)), the substrate concentration resulting in 50% of V(max)(app) (S(50)(app)), and Hill coefficient (n) of 2.10 +/- 0.75 micromol/min/kg, 117 +/- 56 microM, and 1.34 +/- 0.14, respectively. Comparable estimates of V(max)(app) (2.63 +/- 0.33 micromol/min/kg), S(50)(app) (118 +/- 53 microM), and n (2.06 +/- 0.47) describing overall VPA elimination from plasma were obtained by fitting VPA unbound plasma concentration-time data to a two-compartment model with elimination described by the Hill equation. Consistent with our in vivo observations, Eadie-Hofstee plots of VPAG formation in sheep liver microsomes were characteristic of autoactivation kinetics. To our knowledge, these data provide the first clear demonstration that autoactivation kinetics observed in vitro in liver preparations can translate to the in vivo situation at least under certain experimental conditions and confirm its relevance. |
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Authors:
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Harvey Wong; Vincent Tong; K Wayne Riggs; Dan W Rurak; Frank S Abbott; Sanjeev Kumar |
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Publication Detail:
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Type: Journal Article Date: 2007-05-11 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 35 ISSN: 0090-9556 ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2007 Aug |
Date Detail:
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Created Date: 2007-07-20 Completed Date: 2007-11-02 Revised Date: - |
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: 1380-6 Citation Subset: IM |
Affiliation:
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Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, MS 412a, South San Francisco, CA 94080, USA. wong.harvey@gene.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Catalysis Enzyme Activation Female Kinetics Microsomes, Liver / enzymology, metabolism Sheep Valproic Acid / analogs & derivatives*, metabolism*, pharmacokinetics, urine |
| Chemical | |
Reg. No./Substance:
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60113-83-9/valproic acid glucuronide; 99-66-1/Valproic Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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