Effects of CYP2C9*1/*13 on the pharmacokinetics and pharmacodynamics of meloxicam

Abstract

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.

The Measurement of Meloxicam and Meloxicam Metabolites in Rat Plasma Using a High-Performance Liquid Chromatography-Ultraviolet Spectrophotometry Method

“…4,5) These reports suggest that MEL undergoes enterohepatic circulation. Taking these findings into account, we are planning to investigate the process by which MEL is metabolized to 5-HMEL and 5-CMEL (e.g., glucuronide conjugate, CYP metabolism).…”

“…3) Studies of the human plasma concentration/time profile of MEL after a single oral administration indicate that the graph exhibits bimodal peaks. 4,5) These reports suggest that MEL undergoes enterohepatic circulation. Taking these findings into account, we are planning to investigate the process by which MEL is metabolized to 5-HMEL and 5-CMEL (e.g., glucuronide conjugate, CYP metabolism).…”

“…To investigate the PK model of MEL, measurement of the concentrations of MEL and its metabolites (5-HMEL and 5-CMEL) in biological samples is necessary. Several reports have examined the concentration of MEL in human and animal plasma [4][5][6][7][8][9] and the metabolism of MEL. 2,3) However, these studies did not concomitantly measure 5-HMEL and 5-CMEL.…”

Effect of CYP2C9*3 mutant variants on meloxicam pharmacokinetics in a healthy Chinese population

“…In a previous report, the genotype of CYP2C9*1/*13 was associated with decreased metabolism and increased pharmacodynamic effects of meloxicam in Korean subjects (Bae et al, 2011b). However, to the best of our knowledge, there are no reports concerning the relationship between CYP2C9*3 and pharmacodynamic effects of meloxicam in the Chinese population.…”

In Vitro and In Vivo Characterization of 13 CYP2C9 Allelic Variants Found in Chinese Han Population

“…Thereafter, a series of investigations into the catalytic activity of CYP2C9*13 in vivo and in vitro were subsequently performed using tolbutamide, diclofenac, and lornoxicam as the probing substrates (Guo et al, 2005a(Guo et al, , 2005b. Moreover, genetic and clinic investigations in Korea had suggested that the presence of CYP2C9*13 allele statistically resulted in the poor metabolism of losartan and irbesartan after a single oral dose (Li et al, 2009;Choi et al, 2012), and also influenced the pharmacokinetics and pharmacodynamics of meloxicam (Bae et al, 2011). CYP2C9*16(T299A) and CYP2C9*19(Q454H) were discovered after studying 125 Asians from Singapore (Zhao et al, 2004).…”