Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

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 m-, d-and k-opioid receptors. Codeine, morphine, d,l-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 [ 3 H]DAMGO (m-opioid receptor), [ 3 H]DPDPE (d-opioid receptor) and [ 3 H]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 m-opioid receptor. The affinities of dihydromorphine and dihydromorphine-6-O-glucuronide were at least 70 times greater compared with dihydrocodeine (K i 0.3 mmol/ l), whereas the other metabolites yielded lower affinities. For the d-opioid receptor, the order of affinities was similar with the exception that dihydrocodeine-6-O-glucuronide revealed a doubled affinity in relation to dihydrocodeine (K i 5.9 mmol/ 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 (K i 14 mmol/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.The semisynthetic opioid dihydrocodeine is an analgesic and antitussive drug. It exerts its actions by interaction with opioid receptors of different types (m-, d-and k-opioid receptors). Since the beginning of the 1960s dihydrocodeine and dihydrocodeine-containing drugs were used by opioid addicts as a substitute drug to heroin. Recently this use increased by prescribing dihydrocodeine in maintenance treatment of addicts. Individual doses prescribed vary from 60 to 3000 mg dihydrocodeine daily (Frießem & Täschner 1991).Dihydrocodeine, the 7,8-dihydro analogue of codeine, has similar metabolic pathways as codeine (Fromm et al. 1995;Hufschmid et al. 1995). These include O-demethylation to dihydromorphine, formation of the corresponding 6-and/ or 3-O-glucuronides dihydrocodeine-6-O-, dihydromorPart of these results have been presented at

Activation of G-Proteins by Morphine and Codeine Congeners: Insights to the Relevance of O- and N-Demethylated Metabolites at μ- and δ-Opioid Receptors

“…Figure 1 shows the structural simi- larity between dihydrocodeine and its 7,8-unsaturated form, codeine. Table 1 shows that dihydrocodeine was not more potent than codeine, which supports binding data indicating that, like codeine, dihydrocodeine has about 120-fold less affinity for the -receptor compared with its 3-hydroxy analog (Mignat et al, 1995;Schmidt et al, 2002). Again, a possible explanation is that in vivo biotransformation such as N-demethylation or glucuronidation alters the potency of dihydrocodeine.…”

“…For this reason, efficacy and potency profiles were determined for these codeine-based opiates at the ␦-receptor using NG108-15 cells as model system, and compared with their O-and N-demethylated derivatives. Much of the reported receptor binding data indicate that these opioids have much lower affinities for the ␦-receptor than for the -receptor (Mignat et al, 1995;Schmidt et al, 2002). The results shown in Fig.…”

“…Again, a possible explanation is that in vivo biotransformation such as N-demethylation or glucuronidation alters the potency of dihydrocodeine. In a study by Schmidt et al (2002), however, neither nordihydrocodeine nor dihydrocodeine 6-glucuronide exhibited an increase in affinity for -, ␦-, or -receptors. Similarly, Table 1 shows that nordihydrocodeine exhibited no change in potency or efficacy at the -receptor relative to dihydrocodeine.…”

“…Even more surprising is dihydrocodeine, which (like codeine) is reported to have a K i for the -receptor over 100-fold greater than its O-demethylated metabolite dihydromorphine (Schmidt et al, 2002). Studies using human liver microsomes indicate that CYP-2D6 is responsible for the Odemethylation of dihydrocodeine and that EMs have 10 times the clearance rate of PMs (Kirkwood et al, 1997).…”

CYP2D6 in the Metabolism of Opioids for Mild to Moderate Pain

“…Schmidt et al [58] evaluated the affinity of DHC and its metabolites: DHC-6-G, DHM, DHM-3-G, DHM-6-G, NORDHC for -, ␦ -and -opioid receptors in the brain of the guinea pig. All substances displayed the greatest affinity for -opioid receptors, and, with the exception of morphine, the least affinity for -opioid receptors.…”