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Research ArticleArticle

Effects of Cytochrome P450 2C9 Polymorphism on Bosentan Metabolism

Mengchun Chen, Youting Zhang, Peipei Pan, Li Wang, Yunyun Zhan, Hui Jin, Mengmin Xia, Xianqin Wang, Dapeng Dai, Jianping Cai and Guoxin Hu
Drug Metabolism and Disposition November 2014, 42 (11) 1820-1825; DOI: https://doi.org/10.1124/dmd.114.060244
Mengchun Chen
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.)
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Youting Zhang
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.)
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Peipei Pan
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.)
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Li Wang
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.)
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Yunyun Zhan
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.)
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Hui Jin
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.)
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Mengmin Xia
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.)
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Xianqin Wang
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.)
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Dapeng Dai
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.)
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Jianping Cai
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.)
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Guoxin Hu
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.)
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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.

Footnotes

    • Received July 29, 2014.
    • Accepted August 20, 2014.
  • * M.C. and Y.T.Z. contributed equally to this work.

  • This work was supported by the Ministry of Health of the People’s Republic of China [Grant 201302008]; and the National Natural Science Foundation of China [Grant 31371280].

  • dx.doi.org/10.1124/dmd.114.060244.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (11)
Drug Metabolism and Disposition
Vol. 42, Issue 11
1 Nov 2014
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Research ArticleArticle

CYP2C9; Genetic Polymorphism; Bosentan Metabolism

Mengchun Chen, Youting Zhang, Peipei Pan, Li Wang, Yunyun Zhan, Hui Jin, Mengmin Xia, Xianqin Wang, Dapeng Dai, Jianping Cai and Guoxin Hu
Drug Metabolism and Disposition November 1, 2014, 42 (11) 1820-1825; DOI: https://doi.org/10.1124/dmd.114.060244

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Research ArticleArticle

CYP2C9; Genetic Polymorphism; Bosentan Metabolism

Mengchun Chen, Youting Zhang, Peipei Pan, Li Wang, Yunyun Zhan, Hui Jin, Mengmin Xia, Xianqin Wang, Dapeng Dai, Jianping Cai and Guoxin Hu
Drug Metabolism and Disposition November 1, 2014, 42 (11) 1820-1825; DOI: https://doi.org/10.1124/dmd.114.060244
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