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Dihydrocodeine: a new opioid substrate for the polymorphic CYP2D6 in humans
M F Fromm1, U Hofmann, E U Griese
1Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
Clinical Pharmacology and Therapeutics
|October 1, 1995
Summary
Dihydrocodeine (DHC) O-demethylation to dihydromorphine (DHM) is impaired in poor metabolizers of sparteine. The primary elimination pathways for DHC involve the parent compound and its conjugates, regardless of metabolic status.
Area of Science:
- Pharmacology
- Drug Metabolism
- Genetics
Background:
- Dihydrocodeine (DHC) is a widely used analgesic and antitussive.
- Human DHC metabolism data is limited.
- CYP2D6 is hypothesized to catalyze DHC O-demethylation to dihydromorphine (DHM).
Purpose of the Study:
- Investigate DHC metabolic pathways in humans.
- Determine if CYP2D6 metabolizes DHC to DHM.
- Assess the impact of CYP2D6 polymorphism on DHC pharmacokinetics.
Main Methods:
- Administered oral DHC to individuals with varying CYP2D6 activity (extensive, intermediate, poor metabolizers).
- Measured serum DHC and DHM concentrations up to 25 hours.
- Quantified urinary excretion of conjugated and unconjugated DHC, DHM, and nordihydrocodeine.
Main Results:
- DHM formation and clearance were significantly lower in poor metabolizers compared to extensive metabolizers.
- A strong correlation existed between the DHC/DHM ratio and sparteine metabolic ratio.
- No significant differences in parent DHC or nordihydrocodeine excretion were observed between metabolic groups.
Conclusions:
- Dihydrocodeine O-demethylation to dihydromorphine is significantly impaired in poor CYP2D6 metabolizers.
- The primary elimination route for DHC involves the parent drug and its conjugates, irrespective of CYP2D6 genotype.
- CYP2D6 plays a crucial role in the metabolic conversion of DHC to DHM.