Modulation of CYP2E1 activity by isoniazid in rapid and slow N-acetylators.
OBJECTIVE
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.
O'Shea
D
D
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-6600, USA.
Kim
R B
RB
Wilkinson
G R
GR
D000107:Acetylation; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000995:Antitubercular Agents / Q000494:pharmacology*; D002753:Chlorzoxazone / Q000097:blood / Q000378:metabolism* / Q000652:urine; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007538:Isoniazid / Q000494:pharmacology*; D008297:Male; D009125:Muscle Relaxants, Central / Q000097:blood / Q000378:metabolism* / Q000652:urine; D010641:Phenotype
D000995:Antitubercular Agents; D009125:Muscle Relaxants, Central; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone; D007538:Isoniazid