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Phenotypic differences in dextromethorphan metabolism.

S J Vetticaden1, B E Cabana, V K Prasad

  • 1International Drug Registration, Rockville, Maryland 20850.

Pharmaceutical Research
|January 1, 1989
PubMed
Summary
This summary is machine-generated.

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Polymorphic differences in dextromethorphan metabolism were observed in Dutch subjects. Poor metabolizers (PM) showed significantly higher plasma concentrations and altered metabolite profiles compared to extensive metabolizers (EM).

Area of Science:

  • Pharmacogenetics
  • Drug Metabolism
  • Clinical Pharmacology

Background:

  • Dextromethorphan (DM) is a widely used cough suppressant.
  • Individual variability in drug response is often linked to genetic differences in drug metabolism.
  • Previous studies suggested polymorphic metabolism of dextromethorphan.

Purpose of the Study:

  • To investigate polymorphic differences in dextromethorphan metabolism.
  • To characterize the metabolic profiles of poor metabolizers (PM) versus extensive metabolizers (EM) of dextromethorphan.
  • To assess the incidence of poor metabolizers in a Dutch population.

Main Methods:

  • Administration of 60 mg dextromethorphan hydrobromide (OROS tablet) to 44 Dutch subjects.
  • Measurement of plasma concentrations of dextromethorphan and its metabolites (dextrorphan, 3-hydroxymorphinan) at single dose and steady state.

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  • Analysis of urinary drug/metabolite ratios (DMR) and conjugated/free metabolite ratios.

    • Main Results:

    • Plasma concentrations of dextromethorphan were 4-75 times higher in PM compared to EM.
    • Area under the curve (AUC) values for dextromethorphan were significantly higher in PM, while AUCs for dextrorphan and 3-hydroxymorphinan were lower.
    • Urinary DMR indicated significant polymorphism in O-demethylation, but not N-demethylation; PM also showed reduced conjugative capacity.

    Conclusions:

    • Significant genetic polymorphism exists in dextromethorphan O-demethylation, impacting drug and metabolite levels.
    • Poor metabolizers exhibit impaired dextromethorphan clearance and potentially reduced capacity for drug conjugation.
    • The incidence of poor dextromethorphan metabolizers in the studied Dutch population was 9.1%.