Drug metabolic capacity in Koreans : CYP2D6 & CYP2C19 pheno- and genotype relationships in healthy volunteers and in patients

Abstract

This thesis aimed to investigate the relationship between pheno- and genotype of two drugmetabolizing enzymes CYP2D6 and CYYP2C19 in Koreans. Population studies were conducted in healthy volunteers to obtain basic information on these two enzymes. Haloperidol and risperidone were used in psychiatric patients for evaluating the steady state plasma concentrations in relation to the CYP2D6 genotypes. The CYP2C19 genotypes related to pharmacokinetic and pharmacodynamic effects of omeprazole were also studied in patients with acid related diseases after repeated doses.

One hundred and fifty-two healthy Korean volunteers were phenotyped with debrisoquine and the metabolic ratio (MR) varied between 0.09 and 6.3, and all were thus extensive metabolizers. The allele frequency of CYP2D6*10 was 0.51 in this Korean population. The MRs of the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups were significantly different (p<0.0001; Kruskal-Wallis test). It was confirmed that the CYP2D6*10 allele is the major cause of diminished CYP2D6 capacity in Koreans. Omeprazole (20mg orally) was given to 103 healthy Korean subjects and blood was taken 3 h after administration. The plasma omeprazole MRs (omeprazole/hydroxyomeprazole) were bimodally distributed. 13 subjects (12.6%) were identified as poor metabolizers with MR of 6.95 or higher. Allele frequencies of CYP2C19*2 and *3 were 21% and 12%, respectively. The distributions of the omeprazole MRs significantly depend on CYP2C19 genotype status (p<0.0001).

One hundred and twenty Korean schizophrenic patients treated with various, clinically determined, doses of haloperidol (range 3-60, median 20mg/day) in monotherapy were recruited. The concentrations normalized for dose (C/D) of haloperidol in patients with daily doses less than 20mg were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups (One-way ANOVA; p=0.003). However, no difference was found at higher doses. These results suggest the involvement of CYP2D6 in the metabolism of haloperidol at low doses of haloperidol (<20mg daily), while another enzyme, probably CYP3A4, is the most important one at higher doses. 82 Korean schizophrenic patients in monotherapy with oral doses of risperidone from 1 to 8mg/day (mean±SD 4.3±1.9; median 4) were also recruited. The median C/Ds of risperidone showed a statistically significant difference between CYP2D6*1/*1, *1/*10 and *10/*10 groups (Kruskal-Wallis test; p<0.001). For 9-hydroxyrisperidone, an active metabolite, the corresponding median C/Ds were not significantly different between the genotypes (p=0.54). The active moieties (sum of the C/Ds of risperidone and 9-hydroxyrisperidone) were not significantly different between the genotypes (p=0.063). This suggests that the clinical significance of this polymorphism seems to be limited in the case of risperidone.

26 Korean patients with acid related diseases were randomly recruited. The allele frequencies of CYP2C19*2 and *3 Were 35% and 23%, respectively, which are higher than those in the healthy Korean volunteer study. After 8 consecutive doses of 20mg omeprazole, the gastric pH and the plasma gastrin increased significantly in all three CYP2C19 genotypes, which was related to high plasma concentrations of omeprazole. This suggests that repeated "normal" doses of proton pump inhibitors might increase the gastric pH too much in Koreans, in all three CYP2C19 genotype groups.

The CYP2D6*10, CYP2C19*2 and *3 alleles are confirmed to be important for both metabolism and clinical effects of drugs in Koreans. Although the genotypes can predict the activity of CYP2D6 and CYP2C19, the clinical importance is limited, when the enzyme is saturated at high dose as in the case of haloperidol and when active metabolites are formed as in the case of risperidone. Interethnic differences in drug metabolic capacity ought to be considered even when usual doses are used as in the case of omeprazole in Korean patients with acid related disorders.