Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese

Abstract

We examined genetically determined oxidation polymorphisms of metoprolol and mephenytoin in 200 unrelated, healthy Japanese subjects and in 98 mainland Chinese subjects simultaneously. This examination was done according to the respective reported phenotyping criteria by use of the urinary metabolic ratio of metoprolol and of the percentage of excretion of 4-hydroxymephenytoin 8 hours after dose administration. The frequencies of occurrence of poor metabolizers (PMs) in the Japanese versus the Chinese subjects were 0.5% versus 0% for metoprolol and 22.5% versus 17.4% for mephenytoin, respectively. There were no statistically significant differences in these frequencies between the two Oriental populations. However, Chinese extensive metabolizers (EMs) showed a significantly lower excretion of alpha-hydroxymetoprolol (p less than 0.01) and 4-hydroxymephenytoin (p less than 0.001) than that of Japanese EMs, and the mode of the distribution histogram of the Chinese EMs for the two test probes was skewed compared with that of the Japanese EMs. The findings indicate that the two Far Eastern Oriental subject groups have a lower frequency of PM phenotype of debrisoquin/sparteine-type oxidation and a greater incidence of PM phenotype of mephenytoin oxidation compared with the respective frequencies reported from white subjects. However, the explanation for the observation that the metabolic capacities of the test drugs differed between the EMs of the two populations who had a similar ethnic origin and who resided in the same geographic area remains obscure.

Frequency of impaired mephenytoin 4′‐hydroxylation in an Indian population [letter]

“…Nevertheless, it appears that Caucasians and Orientals again differ in the frequency of the PM phenotype, although in the opposite geocentric longitudinal direction to that seen with the debrisoquine/sparteine polymorphism. That is, the incidence of the PM is higher (17.4 to 22.5%) in Japanese (Horai etal., 1989;Nakamura et al, 1985) and Chinese (Horai et al, 1989) than that observed (2.7 to 6.1% ) in Caucasians . The PM trait is apparently absent in Cuna Amerindians (Inaba et al, 1988) but its frequency in populations of other racial origins has not been investigated.…”

“…However, it should be noted that under experimental conditions studied neither of these types of interaction was capable of changing an individual's oxidative phenotype nor were the subjects receiving any drugs at the time of this study. Accordingly, it is likely that the differences in 4'-hydroxylating ability reflect a genetic polymorphism similar to that previously reported in Caucasians, Chinese and Japanese populations (Horai et al, 1989;Nakamura et al, 1985;Wedlund et al, 1984). In this regard, it is interesting that despite the group being relatively small the range of phenotypic trait values of the EM and PM phenotypes in Indians were the same as those found in the other racial groups.…”

“…A major factor for such variability appears to be differences in allelic frequency that have a racial basis. For example, the incidence in Caucasians of different ethnic backgrounds is between 3 and 10% (Eichelbaum & Gross, 1990) whereas the trait is essentially absent in Oriental populations such as Japanese (Horai et al, 1989;Nakamura et al, 1985) and Chinese (Horai et al, 1989;Lou et al, 1987). Intermediate frequencies are present in populations studied in Africa and the sub-continent of India (Eichelbaum & Gross, 1990;Idle & Smith, 1984).…”

Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H2‐receptor antagonist

“…Among North American and European populations, 56.7-81.0% of patients are homo-EMs, 18.0-37.2% are hetero-EMs, and PMs are less than 6.1%, [46][47][48][49][50] and thus omeprazole 40 mg is required to achieve stronger gastric acid suppression than H 2 -RAs. However, in Orientals, homo-EMs are only 27.7-38.2% and the rest of the population has an intermediate or reduced capacity to metabolize omeprazole; 30,[51][52][53] and therefore strong gastric acid suppression can be obtained even with omeprazole 20 mg or less.…”

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

“…About 3 % of Caucasians are PM of S-mephenytoin [8 , 9] and a higher incidence of PMs has been reported in Japanese (18-23 %) [10,11] Chinese (15-17%) [12,13] and in Korean subjects (13-16%) [14]. The PM phenotype is caused by the CYP2C19*2 [15] and CYP2C19*3 alleles although the CYP2C19*3 is very uncommon in Caucasian PMs [16].…”