title: Effects of cytochrome P450 2C9 polymorphism on bosentan metabolism.
abstract: 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.
authors.affiliation: School of Pharmacy of Wenzhou Medical University, Wenzhou (M.C., P.P., L.W., Y.Y.Z., H.J., M.X., X.W., G.H.), the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou (Y.T.Z.), and the Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.D., J.C.).
authors.forename: Mengchun
authors.initials: M
authors.lastname: Chen
authors.affiliation: School of Pharmacy of Wenzhou Medical University, Wenzhou (M.C., P.P., L.W., Y.Y.Z., H.J., M.X., X.W., G.H.), the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou (Y.T.Z.), and the Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.D., J.C.).
authors.forename: Youting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmacy of Wenzhou Medical University, Wenzhou (M.C., P.P., L.W., Y.Y.Z., H.J., M.X., X.W., G.H.), the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou (Y.T.Z.), and the Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.D., J.C.).
authors.forename: Peipei
authors.initials: P
authors.lastname: Pan
authors.affiliation: School of Pharmacy of Wenzhou Medical University, Wenzhou (M.C., P.P., L.W., Y.Y.Z., H.J., M.X., X.W., G.H.), the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou (Y.T.Z.), and the Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.D., J.C.).
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Pharmacy of Wenzhou Medical University, Wenzhou (M.C., P.P., L.W., Y.Y.Z., H.J., M.X., X.W., G.H.), the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou (Y.T.Z.), and the Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.D., J.C.).
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: School of Pharmacy of Wenzhou Medical University, Wenzhou (M.C., P.P., L.W., Y.Y.Z., H.J., M.X., X.W., G.H.), the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou (Y.T.Z.), and the Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.D., J.C.).
authors.forename: Hui
authors.initials: H
authors.lastname: Jin
authors.affiliation: School of Pharmacy of Wenzhou Medical University, Wenzhou (M.C., P.P., L.W., Y.Y.Z., H.J., M.X., X.W., G.H.), the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou (Y.T.Z.), and the Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.D., J.C.).
authors.forename: Mengmin
authors.initials: M
authors.lastname: Xia
authors.affiliation: School of Pharmacy of Wenzhou Medical University, Wenzhou (M.C., P.P., L.W., Y.Y.Z., H.J., M.X., X.W., G.H.), the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou (Y.T.Z.), and the Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.D., J.C.).
authors.forename: Xianqin
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Pharmacy of Wenzhou Medical University, Wenzhou (M.C., P.P., L.W., Y.Y.Z., H.J., M.X., X.W., G.H.), the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou (Y.T.Z.), and the Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.D., J.C.).
authors.forename: Dapeng
authors.initials: D
authors.lastname: Dai
authors.affiliation: School of Pharmacy of Wenzhou Medical University, Wenzhou (M.C., P.P., L.W., Y.Y.Z., H.J., M.X., X.W., G.H.), the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou (Y.T.Z.), and the Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.D., J.C.).
authors.forename: Jianping
authors.initials: J
authors.lastname: Cai
authors.affiliation: School of Pharmacy of Wenzhou Medical University, Wenzhou (M.C., P.P., L.W., Y.Y.Z., H.J., M.X., X.W., G.H.), the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou (Y.T.Z.), and the Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.D., J.C.) hgx@wzmc.edu.cn.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Hu
mesh_terms: D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D000077300:Bosentan; D002681:China; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D005006:Ethnicity; D006801:Humans; D011110:Polymorphism, Genetic; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: D000959:Antihypertensive Agents; D013449:Sulfonamides; D065729:Cytochrome P-450 CYP2C9; D000077300:Bosentan