Document Detail

Inhibition of human liver microsomal epoxide hydrolase by valproate and valpromide: in vitro/in vivo correlation.
MedLine Citation:
PMID:  2501059     Owner:  NLM     Status:  MEDLINE    
On the basis of drug interactions with carbamazepine epoxide, it has been hypothesized that valproic acid and valpromide are inhibitors of epoxide hydrolase, but the role of epoxide hydrolase in these interactions has not been clearly established. In this study, therapeutic concentrations of valproic acid (less than 1 mmol/L) and valpromide (less than 10 mumol/L) inhibited hydrolysis of carbamazepine epoxide and styrene oxide in human liver microsomes and in preparations of purified human liver microsomal epoxide hydrolase. Valpromide (KI = 5 mumol/L) was 100 times more potent than valproic acid (KI = 550 mumol/L) as an inhibitor of carbamazepine epoxide hydrolysis in microsomes. After administration of carbamazepine epoxide to volunteers, the transdihydrodiol formation clearance was decreased 20% by valproic acid (blood concentration approximately 113 mumol/L) and 67% by valpromide (blood concentration less than 10 mumol/L). For both valproic acid and valpromide, a striking similarity exists between in vitro and in vivo inhibitory potencies. Valproic acid and valpromide are the first drugs known to inhibit microsomal epoxide hydrolase, an important detoxification enzyme, at therapeutic concentrations.
B M Kerr; A E Rettie; A C Eddy; P Loiseau; M Guyot; A J Wilensky; R H Levy
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Clinical pharmacology and therapeutics     Volume:  46     ISSN:  0009-9236     ISO Abbreviation:  Clin. Pharmacol. Ther.     Publication Date:  1989 Jul 
Date Detail:
Created Date:  1989-08-17     Completed Date:  1989-08-17     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0372741     Medline TA:  Clin Pharmacol Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  82-93     Citation Subset:  AIM; IM    
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195.
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MeSH Terms
Anticonvulsants / pharmacology*
Carbamazepine / analogs & derivatives,  metabolism
Drug Interactions
Epoxide Hydrolases / antagonists & inhibitors*,  metabolism
Epoxy Compounds / metabolism
Microsomes, Liver / drug effects*,  enzymology
Valproic Acid / analogs & derivatives,  pharmacology*
Grant Support
Reg. No./Substance:
0/Anticonvulsants; 0/Epoxy Compounds; 2430-27-5/dipropylacetamide; 298-46-4/Carbamazepine; 36507-30-9/carbamazepine epoxide; 96-09-3/styrene oxide; 99-66-1/Valproic Acid; EC 3.3.2.-/Epoxide Hydrolases
Erratum In:
Clin Pharmacol Ther 1989 Sep;46(3):343

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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