Document Detail

(+)-N-3-Benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital: new potent and selective in vitro inhibitors of CYP2C19.
MedLine Citation:
PMID:  11854139     Owner:  NLM     Status:  MEDLINE    
Highly potent and selective CYP2C19 inhibitors are not currently available. In the present study, N-3-benzyl derivatives of nirvanol and phenobarbital were synthesized, their respective (+)- and (-)-enantiomers resolved chromatographically, and inhibitor potencies determined for these compounds toward CYP2C19 and other human liver cytochromes P450 (P450s). (-)-N-3-Benzyl-phenobarbital and (+)-N-3-benzyl-nirvanol were found to be highly potent, competitive inhibitors of recombinant CYP2C19, exhibiting K(i) values of 79 and 250 nM, respectively, whereas their antipodes were 20- to 60-fold less potent. In human liver preparations, (-)-N-3-benzyl-phenobarbital and (+)-N-3-benzyl-nirvanol inhibited (S)-mephenytoin 4'-hydroxylase activity, a marker for native microsomal CYP2C19, with K(i) values ranging from 71 to 94 nM and 210 to 280 nM, respectively. At single substrate concentrations of 0.3 microM [(-)-N-3-benzyl-phenobarbital] and 1 microM [(+)-N-3-benzyl-nirvanol] that were used to examine inhibition of a panel of cDNA-expressed P450 isoforms, neither CYP1A2, 2A6, 2C8, 2C9, 2D6, 2E1, nor 3A4 activities were decreased by greater than 16%. In contrast, CYP2C19 activity was inhibited approximately 80% under these conditions. Therefore, (+)-N-3-benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital represent new, highly potent and selective inhibitors of CYP2C19 that are likely to prove generally useful for screening purposes during early phases of drug metabolism studies with new chemical entities.
Hisashi Suzuki; M Byron Kneller; Robert L Haining; William F Trager; Allan E Rettie
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  30     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2002 Mar 
Date Detail:
Created Date:  2002-02-20     Completed Date:  2002-05-20     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  235-9     Citation Subset:  IM    
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington 98195-7610, USA.
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MeSH Terms
Aryl Hydrocarbon Hydroxylases*
Chromatography, High Pressure Liquid
Cytochrome P-450 Enzyme System / antagonists & inhibitors*,  chemistry
DNA, Complementary / metabolism
Enzyme Inhibitors / chemistry,  pharmacology*
Isoenzymes / genetics,  metabolism
Mephenytoin / analogs & derivatives,  chemistry,  pharmacology*
Microsomes, Liver / enzymology
Mixed Function Oxygenases / antagonists & inhibitors*,  chemistry
Phenobarbital / analogs & derivatives,  chemistry,  pharmacology*
Substrate Specificity
Grant Support
Reg. No./Substance:
0/DNA, Complementary; 0/Enzyme Inhibitors; 0/Isoenzymes; 0/N-3-benzylnirvanol; 0/N-3-benzylphenobarbital; 50-06-6/Phenobarbital; 50-12-4/Mephenytoin; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC Hydrocarbon Hydroxylases; EC protein, human

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