The role of active metabolites in dihydrocodeine effects.
OBJECTIVE
The metabolism of dihydrocodeine to dihydromorphine, a high affinity mu-opioid receptor ligand in membrane homogenates, is catalyzed by CYP2D6. However, it is not clear whether an active CYP2D6 enzyme is required for opioid receptor-mediated effects in man after standard dihydrocodeine doses.


METHODS
Whole cell opioid-receptor affinity and effects on cAMP accumulation of dihydrocodeine and its metabolites were determined in differentiated SH-SY5Y neuroblastoma cells. In a double-blind, 2-period, placebo-controlled randomized crossover pilot study the pharmacokinetics of dihydrocodeine (60 mg single dose) and its metabolites were examined in 5 phenotyped extensive (EMs) and 4 poor metabolizers (PMs) for CYP2D6, and pharmacodynamics were evaluated using a pain threshold model and dynamic pupillometry.


RESULTS
Displacement binding and cAMP accumulation experiments showed clearly higher affinities (100- and 50-fold) and activities (180- and 250-fold) of dihydromorphine and dihydromorphine-6-glucuronide, respectively, whereas the other metabolites had similar or lower affinities and activities as compared to dihydrocodeine. The clinical study revealed no significant difference in plasma or urine pharmacokinetics between EMs and PMs for dihydrocodeine and its glucuronide. Dihydromorphine and its glucuronides were detectable in EMs only. A clear reduction of initial pupil diameters was observed up to 6 hours postdose in both PMs and EMs, with no obvious differences between CYP2D6 phenotypes. In the pain threshold model no effects were observed in either group.


CONCLUSIONS
CYP2D6 phenotype has no major impact on opioid receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of CYP2D6 in formation of highly active metabolites.
Schmidt
H
H
Pharmazentrum Frankfurt, Clinical Pharmacology, University of Frankfurt, Germany.
Vormfelde
S V
SV
Walchner-Bonjean
M
M
Klinder
K
K
Freudenthaler
S
S
Gleiter
C H
CH
Gundert-Remy
U
U
Skopp
G
G
Aderjan
R
R
Fuhr
U
U
D000701:Analgesics, Opioid / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001667:Binding, Competitive; D003061:Codeine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D018592:Cross-Over Studies; D000242:Cyclic AMP / Q000096:biosynthesis; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D008297:Male; D008954:Models, Biological; D010146:Pain / Q000188:drug therapy; D010641:Phenotype; D010865:Pilot Projects; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D000242:Cyclic AMP; D019389:Cytochrome P-450 CYP2D6; C014481:dihydrocodeine; D003061:Codeine