Document Detail


Modulation of CYP2E1 activity by isoniazid in rapid and slow N-acetylators.
MedLine Citation:
PMID:  9056059     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: An investigation was undertaken to compare the effects of isoniazid pretreatment on the CYP2E1-mediated 6-hydroxylation of chlorzoxazone in healthy subjects of known N-acetylator phenotype. METHODS: CYP2E1 activity was estimated based on the 6-hydroxylation of chlorzoxazone following single dose (250 mg) oral administration to seven slow and eight rapid N-acetylators who were in good health. Separate studies were performed prior to and 14 days after the subjects received 300 mg isoniazid daily. Additional investigations were undertaken 2 and 16 days after discontinuing treatment with the antitubercular agent. RESULTS: Concomitant administration of chlorzoxazone with the final dose of isoniazid resulted in reduced metabolism in both phenotypes; however, the extent of inhibition of 6-hydroxylation was greater in the slow N-acetylators-about 80% vs 60%. Two days after stopping isoniazid administration, chlorzoxazone's pharmacokinetic parameters had returned to their baseline values and remained constant for a further 14 days in the rapid acetylators. In contrast, chlorzoxazone's 6-hydroxylation in slow acetylators was increased by about 60% compared with baseline at 2 days after discontinuing isoniazid but had returned to its initial value 14 days later. CONCLUSIONS: The interphenotypic difference in the time-dependent interactions of isoniazid with CYP2E1 probably reflect a higher drug exposure in slow acetylators. Inhibition of CYP2E1 activity occurs in both N-acetylator phenotypes but is less extensive in fast acetylators, during the time that effective levels of isoniazid are present in the body. Increased CYP2E1 activity reflective of enzyme induction, on the other hand, is only observable following isoniazid's elimination and is more extensive in slow than rapid acetylators. Even then, however, such induction is relatively modest and of short duration.
Authors:
D O'Shea; R B Kim; G R Wilkinson
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  British journal of clinical pharmacology     Volume:  43     ISSN:  0306-5251     ISO Abbreviation:  Br J Clin Pharmacol     Publication Date:  1997 Jan 
Date Detail:
Created Date:  1997-05-29     Completed Date:  1997-05-29     Revised Date:  2009-10-02    
Medline Journal Info:
Nlm Unique ID:  7503323     Medline TA:  Br J Clin Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  99-103     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-6600, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetylation
Administration, Oral
Adolescent
Adult
Analysis of Variance
Antitubercular Agents / pharmacology*
Chlorzoxazone / blood,  metabolism*,  urine
Cytochrome P-450 CYP2E1 / drug effects*,  metabolism
Enzyme Induction / drug effects
Female
Humans
Hydroxylation
Isoniazid / pharmacology*
Male
Muscle Relaxants, Central / blood,  metabolism*,  urine
Phenotype
Grant Support
ID/Acronym/Agency:
GM-46622/GM/NIGMS NIH HHS; RR-00095/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Antitubercular Agents; 0/Muscle Relaxants, Central; 54-85-3/Isoniazid; 95-25-0/Chlorzoxazone; EC 1.14.14.1/Cytochrome P-450 CYP2E1

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


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