Document Detail

Kinetics of valproic acid glucuronidation: evidence for in vivo autoactivation.
MedLine Citation:
PMID:  17496206     Owner:  NLM     Status:  MEDLINE    
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.
Harvey Wong; Vincent Tong; K Wayne Riggs; Dan W Rurak; Frank S Abbott; Sanjeev Kumar
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Publication Detail:
Type:  Journal Article     Date:  2007-05-11
Journal Detail:
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:
Created Date:  2007-07-20     Completed Date:  2007-11-02     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1380-6     Citation Subset:  IM    
Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, MS 412a, South San Francisco, CA 94080, USA.
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MeSH Terms
Enzyme Activation
Microsomes, Liver / enzymology,  metabolism
Valproic Acid / analogs & derivatives*,  metabolism*,  pharmacokinetics,  urine
Reg. No./Substance:
60113-83-9/valproic acid glucuronide; 99-66-1/Valproic Acid

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