Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

1 The kinetics of codeine and seven of its metabolites codeine-6-glucuronide (C6G), norcodeine (NC), NC-glucuronide (NCG), morphine (M), M-3 (M3G) and 6-glucuronides (M6G), and normorphine (NM) were investigated after a single oral dose of 50 mg codeine phosphate in 14 healthy Caucasian subjects including eight extensive (EM) and six poor (PM) hydroxylators of debrisoquine. The plasma and urine concentrations of codeine and the metabolites were measured by h.p.l.c. 2 The mean area under the curve (AUC), half-life and total plasma clearance of codeine were 1020 ± 340 nmol 1-1 h, 2.58 ± 0.57 h and 2.02 ± 0.73 1 h-1 kg-1, respectively. There were no significant differences between EM and PM in these aspects. 3 PM had significantly lower AUC of M3G, the active metabolites M6G, NM and M (P < 0.0001), and lower partial metabolic clearance by O-demethylation (P < 0.0001). In contrast, the PM had higher AUC of NC (P < 0.05) than the EM. There was no difference between PM and EM in the AUC of C6G and NCG, nor in the partial clearances by N-demethylation and glucuronidation. 4 Among EM, the AUC of C6G was 15 times higher than that of codeine, which in turn was 50 times higher than that of M. The AUCs of M6G and NM were about 6 and 10 times higher than that of M, respectively. The partial clearance by glucuronidation was about 8 and 12 times higher than those by N-and O-demethylations, respectively. 5 The total recovery of drug-related material in 48 h urine collections ranged from 71% to 106% of the dose and did not differ between EM and PM. Six percent of the dose was O-demethylated in EM and the majority of the metabolites produced through this pathway were conjugated. Unconjugated M accounted for less than 0.2% of the dose. In PM, only 0.33% of the dose was metabolized by O-demethylation and M was negligible (0.001% of the dose). However, PM had a significantly higher recovery of NC (P < 0.001) than EM. There was no significant difference between EM and PM in the recovery of codeine, C6G and NCG, and in the renal clearance of codeine or any of its metabolites. 6 Data from a chronic dosing study including three EM and three PM confirmed the results of the single dose study. 7 The clinically important findings were the negligible plasma concentration of the 0-demethylated active metabolites M6G, NM and M in PM, and the relatively high concentrations of M6G and NM in EM. Considering the low plasma concentration of M as well as the potent analgesic effects of M6G and NM, the latter compounds might play an important role in the analgesic effect of codeine.

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.