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Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1.

Publication ,  Journal Article
Kharasch, ED; Thummel, KE; Mhyre, J; Lillibridge, JH
Published in: Clin Pharmacol Ther
June 1993

Disulfiram and its reduced metabolite diethyldithiocarbamate have been identified previously as selective mechanism-based inhibitors of human liver microsomal cytochrome P450 2E1 in vitro. In animals, a single oral dose of disulfiram has been shown to produce a rapid and selective inactivation of hepatic P450 2E1 content and catalytic activity in vivo. This investigation explored the efficacy of single dose disulfiram as an inhibitor of human P450 2E1 activity in vivo. Clinical P450 2E1 activity was assessed by the 6-hydroxylation of chlorzoxazone, a metabolic pathway catalyzed selectively by P450 2E1. Six healthy volunteers received 750 mg oral chlorzoxazone on two occasions in a crossover design, 10 hours after 500 mg oral disulfiram, or after no pretreatment (control subjects). Disulfiram pretreatment markedly decreased chlorzoxazone elimination clearance to 15% of control values (from 3.28 +/- 1.40 to 0.49 +/- 0.07 ml/kg/min, p < 0.005), prolonged the elimination half-life (from 0.92 +/- 0.32 to 5.1 +/- 0.9 hours, p < 0.001), and caused a twofold increase in peak plasma chlorzoxazone concentrations (20.6 +/- 9.9 versus 38.7 +/- 10.3 micrograms/ml, p < 0.001). Disulfiram also profoundly decreased the formation clearance of 6-hydroxychlorzoxazone, from 2.30 +/- 0.93 to 0.17 +/- 0.05 ml/kg/min (p < 0.005). These findings show that a single dose of disulfiram significantly diminishes the activity of human P450 2E1 in vivo. The efficacy of single-dose disulfiram as an inhibitor of human P450 2E1 suggests that this modality for manipulating clinical P450 2E1 activity may provide a useful probe for delineating P450 2E1 participation in human drug biotransformation or for the treatment of poisoning by P450 2E1-activated toxins.

Duke Scholars

Published In

Clin Pharmacol Ther

DOI

ISSN

0009-9236

Publication Date

June 1993

Volume

53

Issue

6

Start / End Page

643 / 650

Location

United States

Related Subject Headings

  • Random Allocation
  • Pharmacology & Pharmacy
  • Oxidoreductases, N-Demethylating
  • Male
  • Hydroxylation
  • Humans
  • Drug Interactions
  • Down-Regulation
  • Disulfiram
  • Cytochrome P-450 Enzyme System
 

Citation

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Kharasch, E. D., Thummel, K. E., Mhyre, J., & Lillibridge, J. H. (1993). Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1. Clin Pharmacol Ther, 53(6), 643–650. https://doi.org/10.1038/clpt.1993.85
Kharasch, E. D., K. E. Thummel, J. Mhyre, and J. H. Lillibridge. “Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1.Clin Pharmacol Ther 53, no. 6 (June 1993): 643–50. https://doi.org/10.1038/clpt.1993.85.
Kharasch ED, Thummel KE, Mhyre J, Lillibridge JH. Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1. Clin Pharmacol Ther. 1993 Jun;53(6):643–50.
Kharasch, E. D., et al. “Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1.Clin Pharmacol Ther, vol. 53, no. 6, June 1993, pp. 643–50. Pubmed, doi:10.1038/clpt.1993.85.
Kharasch ED, Thummel KE, Mhyre J, Lillibridge JH. Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1. Clin Pharmacol Ther. 1993 Jun;53(6):643–650.
Journal cover image

Published In

Clin Pharmacol Ther

DOI

ISSN

0009-9236

Publication Date

June 1993

Volume

53

Issue

6

Start / End Page

643 / 650

Location

United States

Related Subject Headings

  • Random Allocation
  • Pharmacology & Pharmacy
  • Oxidoreductases, N-Demethylating
  • Male
  • Hydroxylation
  • Humans
  • Drug Interactions
  • Down-Regulation
  • Disulfiram
  • Cytochrome P-450 Enzyme System