AimsTo determine the frequencies of the variant alleles and the genotypes of CYP2C9 in a Korean population. MethodsThree hundred and fifty-eight healthy Korean subjects were studied. CYP2C9 alleles were detected by polymerase chain reaction-restriction fragment leng th polymorphism assays and direct sequencing assays. ResultsThe allele frequencies were 0.934 for CYP2C9 * 1 , 0.060 for CYP2C9 * 3 and 0.006 for CYP2C9 * 13 . The CYP2C9*2, * 4, * 5 and * 11 alleles were not detected. The frequencies of the CYP2C9 * 1/ * 1 , * 1/ * 3 and * 1/ * 13 genotypes were 0.869, 0.120 and 0.011, respectively. ConclusionThe frequency of the CYP2C9 * 3 allele in the Korean population studied was significantly higher than reported elsewhere, and a novel allele, CYP2C9 * 13 , was found at a frequency of 0.006 (95% confidence interval 0, 0.012). Only three genotypes of CYP2C9, CYP2C9

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Meloxicam is a substrate for the CYP2C9 and CYP3A4 enzymes. • We have previously reported that the frequency of the CYP2C9*1/*13 genotype in the Korean population is 1.1%. WHAT THIS STUDY ADDS • The CYP2C9*1/*13 genotype is associated with decreased metabolism and increased pharmacodynamic effects of meloxicam. • This is the first report that evaluates the in vivo effects of the CYP2C9*13 allele on the pharmacokinetics and pharmacodynamics of CYP2C9 substrates with a sufficient sample size. AIMS To determine the effects of the CYP2C9*1/*13 genotype on the pharmacokinetics and pharmacodynamics of meloxicam in Korean subjects. METHODS Meloxicam (15 mg) was orally administered to 21 healthy Korean volunteers with either the CYP2C9*1/*1 or the CYP2C9*1/*13 genotype. Plasma meloxicam concentrations were analysed by HPLC‐UV for 72 h after drug administration. The pharmacodynamic effects of meloxicam were determined by measuring TXB2 generated in blood. RESULTS The AUC(0,∞) and Cmax of meloxicam were 2.43‐ and 1.46‐fold higher in the CYP2C9*1/*13 group than in the CYP2C9*1/*1 group, respectively. The oral clearance of meloxicam was significantly lower in the CYP2C9*1/*13 group (37.9% of wild type) than in the CYP2C9*1/*1 group. The t1/2 of meloxicam was 1.84‐fold longer in the CYP2C9*1/*13 group than in the CYP2C9*1/*1 group. The rate of TXB2 production was significantly lower in the CYP2C9*1/*13 group than in the CYP2C9*1/*1 group. CONCLUSIONS The CYP2C9*1/*13 genotype is associated with decreased metabolism and increased pharmacodynamic effects of meloxicam.

No abstract

Cytochrome P450 (CYP) 2D6 is present in less than about 2% of all CYP enzymes in the liver, but it is involved in the metabolism of about 25% of currently used drugs. CYP2D6 is the most polymorphic among the CYP enzymes. We determined alleles and genotypes of CYP2D6 in 3417 Koreans, compared the frequencies of CYP2D6 alleles with other populations, and observed the differences in pharmacokinetics of metoprolol, a prototype CYP2D6 substrate, depending on CYP2D6 genotype. A total of 3417 unrelated healthy subjects were recruited for the genotyping of CYP2D6 gene. Among them, 42 subjects with different CYP2D6 genotypes were enrolled in the pharmacokinetic study of metoprolol. The functional allele *1 and *2 were present in frequencies of 34.6 and 11.8%, respectively. In decreased functional alleles, *10 was the most frequent with 46.2% and *41 allele was present in 1.4%. The nonfunctional alleles *5 and *14 were present at 4.5 and 0.5% frequency, respectively. The *X × N allele was present at a frequency of 1.0%. CYP2D6*1/*1, *1/*2 and *2/*2 genotypes with normal enzyme activity were present in 12.1%, 8.6% and 1.4% of the subjects, respectively. CYP2D6*5/*5, *5/*14, and *14/*14 genotypes classified as poor metabolizer were only present in 4, 2, and 1 subjects, respectively. Mutant genotypes with frequencies of more than 1% were CYP2D6*1/*10 (32.0%), *10/*10 (22.3%), *2/*10 (11.7%), *5/*10 (3.7%), *1/*5 (2.5%), and *10/*41 (1.2%). The relative clearance of metoprolol in CYP2D6*1/*10, *1/*5, *10/*10, *5/*10, and *5/*5 genotypes were 69%, 57%, 24%, 14% and 9% of CYP2D6*wt/*wt genotype, respectively. These results will be very useful in establishing a strategy for precision medicine related to the genetic polymorphism of CYP2D6.

These results indicate that CYP2C9*3/*3 individuals may be at a higher risk for concentration-dependent adverse effects during long-term treatment with standard doses of meloxicam.