Codeine O‐demethylation co‐segregates with polymorphic debrisoquine hydroxylation.

Abstract

1 A single oral dose of codeine (25 mg) was given to 132 healthy Swedish Caucasians who had previously been phenotyped with respect to debrisoquine hydroxylation. The 'metabolic ratios' (MR) in urine of codeine O-demethylation (codeine/(morphine (M) + morphine-3-and 6-glucuronides (M3G and M6G) + normorphine)), N-demethylation (codeine/(norcodeine (NC) + norcodeine glucuronide + normorphine (NM))) and glucuronidation (codeine/codeine-6-glucuronide (C6G)) were calculated following h.p.l.c. analysis of urine samples collected over 8 h. 2 There was a significant correlation between the log MR for debrisoquine hydroxylation and the log MR for codeine O-demethylation (r, = 0.77, P < 0.001). The poor debrisoquine hydroxylators had MRs of codeine O-demethylation between 8.3 and 55.1, while the values for extensive hydroxylators were between 0.4 and 5.5. 3 The poor debrisoquine hydroxylators excreted significantly less M, M3G, M6G and NM, while the urinary recovery of C6G and NC was significantly higher in these subjects compared to the extensive hydroxylators. 4 The MRs for glucuronidation and N-demethylation did not exhibit a bimodal distribution, and were not related to the MR of debrisoquine hydroxylation. 5 No associations were found between sex, body-weight, smoking habits, age, urine volume or urine pH and the O-demethylation of codeine. 6 The O-demethylation of codeine to form M appears to be under the same polymorphic genetic control as the 4-hydroxylation of debrisoquine.

Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.

“…In adults codeine is predominantly metabolised by glucuronidation but may also undergo N-and 0-demethylation to form norcodeine and morphine, respectively. A genetic polymorphism in 0-demethylation has been shown in adult healthy volunteers (Chen et al, 1988, Yue et al, 1989 and in vitro using liver biopsies (Dayer et al, 1988;Mortimer et al, 1990). In foetal human liver microsomes codeine 0-demethylation does not occur while N-demethylation is comparable with that in adults (Ladona et al, 1989).…”

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

“…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).…”

Population pharmacokinetics of nortriptyline during monotherapy and during concomitant treatment with drugs that inhibit CYP2D6‐an evaluation with the nonparametric maximum likelihood method.

“…To qualify for these groups at least one of the following criteria was required: 1) The drug is an inhibitor of CYP2D6 in vitro [22]; 2) The drug has an inhibitory effect in vivo on debrisoquine/sparteine hydroxylation [23][24][25][26]; 3) The drug is dependent on CYP2D6 for its own metabolism [11,[27][28][29][30][31][32]. Table 2 summarizes the data on the interacting drugs.…”