Interindividual and interethnic differences in the demethylation and glucuronidation of codeine.

Abstract

1 The 8 h urinary excretion of codeine and seven of its metabolites was compared in 149 healthy Swedish Caucasians and 133 healthy Chinese following a single oral dose of 25 mg codeine phosphate. 2 The total 8 h urinary recovery of drug-related material was 74 ± 24% in the Caucasians and 60 ± 14% in the Chinese (P < 0.001). The excretion of unchanged codeine was significantly higher in the Chinese (7.2%) compared with the Caucasians (4.3%, P < 0.001). 3 The Caucasians excreted significantly greater proportions of codeine-6-glucuronide (C6G) (62%) than the Chinese (44%) (P < 0.001). The frequency distribution of the log metabolic ratio (MR) for glucuronidation (codeine/C6G) was shifted towards higher values in the Chinese population. Males in both groups and Chinese smokers had significantly lower glucuronidation MRs than females and non-smokers in the respective populations (P < 0.001). 4 The frequency distribution of the MR for O-demethylation (codeine/morphine (M) + M-3 and M-6-glucuronide (M3G and M6G) + normorphine (NM) was highly skewed in the Caucasians, suggestive of a bimodal distribution. There was a 160-fold interindividual variation in this MR. A unimodal distribution of the log O-demethylation MR was observed in Chinese. The Caucasians excreted less M and more M6G than did the Chinese (P < 0.001). 5 Significantly more norcodeine (NC) and less NC-glucuronide (NCG) were excreted in the Chinese compared with the Caucasians (P < 0.001). The mean value of the N-demethylation MR was higher in Chinese (P < 0.001), with a 17-fold interindividual variation in both populations. 6 The reproducibility of the indices of codeine metabolism was tested in 25 individuals. The correlation coefficients between measurements taken on two occasions were 0.92, 0.77 and 0.79 for the MRs of 0-and N-demethylations and glucuronidation, respectively (P < 0.001). MRs measured in 8 h urine collections were similar to those in urine collected over 24h. 7 Pronounced interethnic differences were shown in the metabolism of codeine. Compared with Caucasians, the Chinese were less able to metabolise codeine, in particular, by glucuronidation. However, as observed with debrisoquine, the occurrence of genetically poor 0-demethylators of codeine was rare in the Chinese compared with the Caucasians. Keywords codeine metabolism glucuronidation demethylation ethnic differences Caucasians Chinese 629 630 Q. Y. Yue et al.

Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

“…Codeine glucuronidation was decreased in Han Chinese when compared to a Swedish population (22). Paracetamol glucuronidation in small Chinese and Caucasian groups has been compared but no interethnic differences were observed (23).…”

Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.

“…Glucuronidation of ethylmorphine to ethylmorphine-6-glucuronide was the major metabolic pathway constituting 28 ronidation was found to be the second most important transformation in eight subjects with at MRo < 0.7, representing about 15% of the given dose. The variation among all 10 subjects was nine-fold with respect to the formation of the pharmacologically active metabolites morphine and morphine-6-glucuronide.…”

“…Furthermore, this CYP2D6 pathway is minor to glucuronidation, and about equivalent in importance to the N-demethylation which is mediated by a member of the CYP3A subfamily [24]. A wide variation in activity exists for both CYP3A and UDPGT [25][26][27][28]. Thus, activity in the alternative metabolic pathways could greatly influence the amount of ethylmorphine available for 0-deethylation, and thus influence the amount of morphine and morphine-glucuronides formed.…”

Summer Day/Night Gender Differences in Serum Total Antioxidant Capacity as a Methodological Pitfall in Human Antioxidant Research

“…Therefore, high inter individual and low intra individual variability have been reported in biological measures (Yue et al, 1989;Cope et al, 2013). Free radicals (FRs) are compounds with unpaired electrons or an open shell configuration that may have positive, negative, or zero charge.…”

“…Researching on human biological markers is a difficult task because several biological variables present data that depend on demographic and individual factors such as gender, ethnic group or chronotype, among others (Yue et al, 1989;MoreraFumero et al, 2013). Therefore, high inter individual and low intra individual variability have been reported in biological measures (Yue et al, 1989;Cope et al, 2013).…”