Affinities of dihydrocodeine and its metabolites to opioid receptors.

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Schmidt H, Vormfelde Sv, Klinder K, Gundert-Remy U, Gleiter CH, Skopp G, Aderjan R, Fuhr U

Affinities of dihydrocodeine and its metabolites to opioid receptors.

Pharmacol Toxicol. 2002 Aug;91(2):57-63.

PubMed ID

12420793 [ View in PubMed

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Abstract

Dihydrocodeine is metabolized to dihydromorphine, dihydrocodeine-6-O-, dihydromorphine-3-O- and dihydromorphine-6-O-glucuronide, and nordihydrocodeine. The current study was conducted to evaluate the affinities of dihydrocodeine and its metabolites to mu-, delta- and kappa-opioid receptors. Codeine, morphine, d,1-methadone and levomethadone were used as controls. Displacement binding experiments were carried out at the respective opioid receptor types using preparations of guinea pig cerebral cortex and the specific opioid agonists [5H]DAMGO (mu-opioid receptor), [3H]DPDPE (delta-opioid receptor) and [3H]U69,593 (K-opioid receptor) as radioactive ligands at concentrations of 0.5, 1.0 and 1.0 nmol/l, respectively. All substances had their greatest affinity to the mu-opioid receptor. The affinities of dihydromorphine and dihydromorphine-6-O-glucuronide were at least 70 times greater compared with dihydrocodeine (Ki 0.3 micromol/l), whereas the other metabolites yielded lower affinities. For the delta-opioid receptor, the order of affinities was similar with the exception that dihydrocodeine-6-O-glucuronide revealed a doubled affinity in relation to dihydrocodeine (Ki 5.9 micromol/l). In contrast, for the K-opioid receptor, dihydrocodeine-6-O- and dihydromorphine-6-O-glucuronide had clearly lower affinities compared to the respective parent compounds. The affinity of nordihydrocodeine was almost identical to that of dihydrocodeine (Ki 14 micromol/l), whereas dihydromorphine had a 60 times higher affinity. These results suggest that dihydromorphine and its 6-O-glucuronide may provide a relevant contribution to the pharmacological effects of dihydrocodeine. The O-demethylation of dihydrocodeine to dihydromorphine is mediated by the polymorphic cytochrome P-450 enzyme CYP2D6, resulting in different metabolic profiles in extensive and poor metabolizers. About 7% of the caucasian population which are CYP2D6 poor metabolizers thus may experience therapeutic failure after standard doses.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Codeine	Delta-type opioid receptor	Protein	Humans	Yes	Agonist	Details
Codeine	Kappa-type opioid receptor	Protein	Humans	Yes	Agonist	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Dihydrocodeine	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate	Details