TY - JOUR T1 - Effects of Cytochrome P450 2C9 Polymorphism on Bosentan Metabolism JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1820 LP - 1825 DO - 10.1124/dmd.114.060244 VL - 42 IS - 11 AU - Mengchun Chen AU - Youting Zhang AU - Peipei Pan AU - Li Wang AU - Yunyun Zhan AU - Hui Jin AU - Mengmin Xia AU - Xianqin Wang AU - Dapeng Dai AU - Jianping Cai AU - Guoxin Hu Y1 - 2014/11/01 UR - http://dmd.aspetjournals.org/content/42/11/1820.abstract N2 - Cytochrome P450 (P450) 2C9 is an important member of the P450 enzyme superfamily, with 58 CYP2C9 allelic variants previously reported. Genetic polymorphisms of CYP2C9 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. The aim of this study was to assess the catalytic activities of 38 human CYP2C9 alleles, including 24 novel alleles (*36–*60) found in the Han Chinese population, toward bosentan (BOS) in vitro. Insect microsomes expressing the 38 CYP2C9 alleles were incubated with 10–625 μM bosentan for 30 minutes at 37°C and terminated by cooling to −80°C immediately. BOS and hydroxyl bosentan, the major metabolite of BOS, were analyzed by ultra-performance liquid chromatography–tandem mass spectrometry system. Thirty-eight defective alleles can be classified into three categories according to the relative clearance value compared with wild type: nine alleles exhibited significantly increased intrinsic clearance values (Vmax/Km) compared with the wild type (1.5-fold–∼4.9-fold relative clearance); nine alleles exhibited significantly reduced intrinsic clearance values compared with the wild type (0.6–28.9% relative clearance). The remaining 20 alleles exhibited no significant difference (1-fold) in enzyme activity compared with the wild type. These findings suggest that more attention should be directed to subjects carrying these infrequent CYP2C9 alleles when administering BOS in the clinic. This is the first report of all these rare alleles for BOS metabolism, providing fundamental data for further clinical studies on CYP2C9 alleles. ER -