Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: Relationship to the presence of immunoidentified cytochrome P-450IID1

Abstract

We studied the oxidation capacity in liver biopsies of a series of extensive metabolizers (n = 10) and poor metabolizers (n = 2) as identified by in vivo phenotyping with dextromethorphan. Codeine and dextromethorphan were used as probe drugs in vitro. The data were compared with the contents of cytochrome P-450IID1 as quantitated by Western immunoblotting by use of a specific monoclonal antibody (MAb 114/2). The O-demethylation of codeine was highly correlated with the O-demethylation of dextromethorphan (r = 0.90). The N-demethylation of codeine was catalyzed at a considerably higher rate than the O-demethylation. The N-demethylation to O-demethylation ratio of codeine was 46 in the poor metabolizer and, on average, 6.2 (range, 2.6 to 11) in the extensive metabolizers, respectively. The band intensity in Western blots correlated with the rate of O-demethylation of codeine (r = 0.95) and of dextromethorphan (r = 0.88) in the extensive metabolizers. The comeasurement of the O-demethylation and N-demethylation of codeine may provide a tool with which to phenotype individuals in vitro with respect to the polymorphism of the cytochrome P-450IID1.

Differential foetal development of the O‐ and N‐demethylation of codeine and dextromethorphan in man.

“…Our observation that the inter-individual variation in O-demethylation is different from that in the N-demethylation of codeine and dextromethorphan (Mortimer et al, 1990) gives support to this contention.…”

“…Other populations, like Ghanaians, appear to have a metabolic pattern similar to Caucasians concerning debrisoquine metabolism, but the PMs of this population show high metabolic activities for sparteine (Eichelbaum & Woolhouse, 1985;Woolhouse, 1986). Recently, codeine was reported to be subject to this polymorphism (Chen et al, 1988;Dayer et al, 1988;Mortimer et al, 1990;Yue et al, 1989). In a series of extensive metabolisers (EM), morphine formation from codeine correlated well with the immunodetected protein in Western blots using a monoclonal antibody (MAb) 114/2 against human P450 IID6 (Mortimer et al, 1990).…”

“…analysis of the dextrorphan, 3-methoxymorphinan and 3-OH-morphinan metabolites were performed as described previously for adult human liver microsomes (Mortimer et al, 1990 Inhibition studies Potential drug substrates of P450 IIIA (midazolam, cyclosporine A, quinidine) (Guengerich et al, 1986;Kronbach et al, 1988Kronbach et al, , 1989 were added at concentrations of 50 and 500 FM to inhibit codeine N-demethylation. Propafenone, reported to be an inhibitor of P450 IID6 (Kroemer et al, 1989;Siddoway et al, 1987), was also tested at the above concentration range.…”

“…Both compounds are also N-demethylated, to 3-methoxymorphinan (3-MM) and norcodeine (NC), respectively; these reactions have a greater quantitative importance in vitro in human liver microsomes (Mortimer et al, 1990). In codeine treated patients NC is the major oxidised metabolite in plasma (Persson et al, 1991).…”

Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication

“…1 A strong correlation between debrisoquine metabolic ratio (MR), reflecting CYP2D6 activity, and the urinary recovery of codeine and its metabolites formed by O-and N-demethylation has been shown. 2 Poor metabolizers (PM) lacking CYP2D6 activity had extremely low plasma concentrations and urinary recovery rates of morphine and morphine glucuronides [2][3][4][5] and very little analgesic efficacy of codeine. 6,7 Correspondingly, they may have a lower risk of developing codeine addiction because the active principle acting at the m-opioid receptors is lacking.…”