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Related Experiment Videos

Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation.

Q Y Yue1, J O Svensson, C Alm

  • 1Department of Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, Sweden.

British Journal of Clinical Pharmacology
|December 1, 1989
PubMed
Summary
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Codeine O-demethylation is genetically controlled, similar to debrisoquine hydroxylation. Poor metabolizers of debrisoquine show reduced codeine O-demethylation, impacting morphine and normorphine excretion.

Area of Science:

  • Pharmacogenetics
  • Drug Metabolism
  • Human Genetics

Background:

  • Codeine is a widely used analgesic.
  • Individual differences in codeine metabolism can affect its efficacy and safety.
  • Debrisoquine 4-hydroxylation is a well-established probe for CYP2D6 activity, a key enzyme in drug metabolism.

Purpose of the Study:

  • To investigate the relationship between debrisoquine hydroxylation phenotype and codeine metabolism.
  • To determine if codeine O-demethylation is subject to the same polymorphic genetic control as debrisoquine 4-hydroxylation.

Main Methods:

  • 132 healthy Swedish Caucasians received a single oral dose of codeine (25 mg).
  • Urine samples were collected over 8 hours and analyzed using HPLC.
  • Metabolic ratios (MR) for codeine O-demethylation, N-demethylation, and glucuronidation were calculated.

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Main Results:

  • A significant correlation was found between log MR for debrisoquine hydroxylation and codeine O-demethylation (rs = 0.77, P < 0.001).
  • Poor debrisoquine hydroxylators exhibited significantly higher codeine O-demethylation MRs compared to extensive hydroxylators.
  • Poor hydroxylators excreted less morphine and normorphine, but more codeine-6-glucuronide and norcodeine.

Conclusions:

  • Codeine O-demethylation to morphine is under the same polymorphic genetic control as debrisoquine 4-hydroxylation.
  • CYP2D6 genotype likely influences codeine metabolism and subsequent analgesic response.
  • These findings have implications for personalized medicine and optimizing codeine therapy.