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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.
Background:
The opioid dihydrocodeine (DHC) is frequently used as an analgesic and antitussive agent. However, until now there have been no detailed data on dihydrocodeine metabolism in humans. We therefore investigated pathways that contribute to elimination of dihydrocodeine, and we tested the hypothesis that dihydrocodeine O-demethylation to dihydromorphine (DHM) is catalyzed by the polymorphic CYP2D6.
Methods:
A single oral dose of dihydrocodeine was administered to six extensive (metabolic ratio [MR] < or = 1), two intermediate (1 < MR < 20) and six poor metabolizers (MR > or = 20) of sparteine/debrisoquin. Serum concentrations of dihydrocodeine and dihydromorphine were measured up to 25 hours, and urinary excretion of conjugated and unconjugated dihydrocodeine, dihydromorphine, and nordihydrocodeine were determined.
Results:
There were no differences in the pharmacokinetics of dihydrocodeine between extensive and poor metabolizers. However, the area under the serum concentration-time curve (AUC), partial metabolic clearance, and total urinary recovery of dihydromorphine were significantly lower in poor metabolizers (10.3 +/- 6.1 nmol.hr/L; 7.0 +/- 4.1 ml/min; 1.3% +/- 0.9% of dose) compared with extensive metabolizers (75.5 +/- 42.9 nmol.hr/L; 49.7 +/- 29.9 ml/min; 8.9% +/- 6.2%; p < 0.01). There was a strong correlation between the AUCDHC/AUCDHM ratio and the urinary metabolic ratio of sparteine (rS = 0.89, p = 0.001). No significant differences between extensive and poor metabolizers were detected in urine for conjugated dihydrocodeine (extensive metabolizers, 27.7% of dose; poor metabolizers, 31.5%), unconjugated dihydrocodeine (extensive metabolizers, 31.1%; poor metabolizers, 31.1%), conjugated nordihydrocodeine (extensive metabolizers, 6.3%; poor metabolizers, 5.4%), or unconjugated nordihydrocodeine (extensive metabolizers, 15.8%; poor metabolizers, 19.5%).
Conclusions:
Dihydrocodeine O-demethylation to dihydromorphine is impaired in poor metabolizers of sparteine. The main urinary metabolites after administration of dihydrocodeine are the parent compound and its conjugates in extensive and poor metabolizers.
Insights
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.