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Related Experiment Videos

Single-dose disulfiram does not inhibit CYP2A6 activity

E D Kharasch1, D C Hankins, P J Baxter

  • 1Department of Anesthesiology, University of Washington, Seattle 98195, USA. kharasch@u.washington.edu

Clinical Pharmacology and Therapeutics
|August 8, 1998
PubMed
Summary

Single-dose disulfiram does not inhibit human CYP2A6 activity in vivo. This finding is crucial for using disulfiram as a probe to study drug metabolism, indicating it specifically targets CYP2E1.

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Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Enzyme Inhibition

Background:

  • Disulfiram and diethyldithiocarbamate inhibit human cytochrome P450 2E1 (CYP2E1) in vitro.
  • Single-dose disulfiram diminishes CYP2E1 activity in vivo, used as a probe for drug metabolism.
  • The in vivo specificity of disulfiram for CYP2E1 versus CYP2A6 is not well-established.

Purpose of the Study:

  • To investigate the effect of a single oral dose of disulfiram on human CYP2A6 activity in vivo.
  • To determine if disulfiram's inhibitory effects extend to CYP2A6, beyond its known inhibition of CYP2E1.

Main Methods:

  • CYP2A6 activity was assessed by measuring the 7-hydroxylation of coumarin, a selective CYP2A6 substrate.
  • Ten healthy volunteers participated in a randomized crossover study, receiving either disulfiram or a placebo before coumarin administration.

Related Experiment Videos

  • Plasma and urine concentrations of coumarin and 7-hydroxycoumarin were quantified using High-Performance Liquid Chromatography (HPLC).

    • Main Results:

    • Disulfiram pretreatment did not significantly alter the area under the plasma 7-hydroxycoumarin curve.
    • Key pharmacokinetic parameters of 7-hydroxycoumarin, including Cmax and Tmax, remained unchanged after disulfiram administration.
    • Total urinary excretion of 7-hydroxycoumarin over 24 hours was not diminished by disulfiram pretreatment.

    Conclusions:

    • A single dose of disulfiram does not inhibit human CYP2A6 activity in vivo.
    • Disulfiram can be reliably used as an in vivo probe to indicate CYP2E1 involvement in drug metabolism, but not CYP2A6.
    • These findings clarify the specificity of disulfiram as a pharmacological tool in drug metabolism studies.