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Dihydrocodeine: A new opioid substrate for the polymorphic CYP2D6 in humans
Author(s) -
Fromm Martin F.,
Hofmann Ute,
Griese ErnstUlrich,
Mikus Gerd
Publication year - 1995
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/0009-9236(95)90049-7
Subject(s) - chemistry , codeine , cyp2d6 , pharmacology , analgesic , pharmacokinetics , urine , morphine , metabolism , medicine , cytochrome p450 , biochemistry
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]≤1), two intermediate (1 < MR < 20) and six poor metabolizers (MR ≥ 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 AUC DHC AUC DHM ratio and the urinary metabolic ratio of sparteine ( r S = 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. Clinical Pharmacology & Therapeutics (1995) 58 , 374–382; doi: