We examined metoprolol oxidation capacity in 218 unrelated, healthy Korean subjects using the 8 h urinary metabolic ratio (MR) of metoprolol to ot-hydroxymetoprolol after an oral dose of 100 mg metoprolol tartrate. The results were compared with those from 295 Japanese and 107 mainland Chinese whose metoprolol oxidation capacities were assessed in a similar manner. The frequency of occurrence of poor metabolisers (PMs) was 0.5% (1/218) in the Korean, 0.7% (2/295) in the Japanese and 0% in the Chinese population. However, the respective mean (± s.d.) MRs (0.84 ± 1.14 and 0.87 ± 0.90) in the Korean and Japanese extensive metabolisers (EMs) were significantly (P < 0.001) less than that in the Chinese EMs (2.81 ± 2.35), and the mode of the distribution histogram and the probit plot of data for Chinese EMs were shifted to the right compared with those for Korean and Japanese EMs. The results indicate that Koreans, like Japanese and mainland Chinese, have a much lower frequency of the PM phenotype of debrisoquine/ sparteine-type oxidation compared with that reported for Caucasian populations. Chinese EMs appear to have a lower capacity to metabolise metoprolol to a-hydroxymetoprolol compared with Korean or Japanese EMs.

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We examined dapsone N-acetylation and metoprolol alpha-hydroxylation and S-mephenytoin 4-hydroxylation phenotypings using the respective test probes (dapsone and racemic metoprolol and mephenytoin) administered separately and in a cocktail manner to an Indonesian subject group (n = 30). After ascertaining that the separate and cocktail phenotyping tests of the probe drugs correlated with each other (all rs values > 0.84; p < 0.001), the cocktail phenotyping assessment was extended to the other 74 Indonesians. In a total of 104 Indonesians phenotyped with the cocktail test, a visual antimode was apparent only in the dapsone N-acetylation and S-mephenytoin 4-hydroxylation polymorphisms: the frequencies of slow acetylators and poor hydroxylators were 43.3% (95% confidence interval, 33.7% to 52.8%) and 15.4% (95% confidence interval, 8.5% to 22.3%), respectively. The distribution histogram and probit plots of the metabolic ratio of metoprolol gave no clear evidence for bimodality, and therefore no poor alpha-hydroxylator of metoprolol was considered to exist in the present sample size. The findings indicate that the Indonesian subjects have a greater incidence of slow acetylator phenotype compared with Japanese and Chinese, as well as a frequency of poor metabolizer phenotype of S-mephenytoin similar to that of Korean and Chinese subjects. They resemble an African population (Nigerians) in metoprolol alpha-hydroxylation polymorphism, with no apparent antimode derived from white populations.

1 The metabolism of proguanil (PG) was studied by measuring PG, cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) in plasma and urine samples after an oral 200 mg dose of PG hydrochloride administered to 14 extensive (EMs) and 10 poor hydroxylators (PMs) of S-mephenytoin of Indonesian origin.2 The mean (± s.d.) values of the elimination half-life (ti/2) and AUC of PG were significantly (P < 0.01) greater in the PM than in the EM group (20.6 ± 3.1 vs 14.6 ± 3.5 (95% confidence intervals of difference 3.1 to 8.9) h; and 5.43 ± 1.89 vs 3.68 ± 0.83 (0.58 to 2.91) gg ml-1 h).3 Plasma concentrations of CG, an active metabolite, could not be detected in all PMs, and those of CPB were sufficiently high to determine a time-course in only four PMs. Mean AUC(0,24 h) values of CPB were significantly (P < 0.05) lower in the PM (n = 4) than in the EM group (n = 14) (0.47 ± 0.13 vs 0.88 ± 0.50 (-0.14 to 0.96) ,ug ml-1 h). (rs = -0.831) metabolic ratios.6 The bioactivation of PG to CG cosegregates with the genetically determined 4'-hydroxylation polymorphism of S-mephenytoin in Indonesian subjects, and the formation of CPB appears to be associated partially with S-mephenytoin 4'-hydroxylation.

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