In vivo Evaluation of Coumarin and Nicotine as Probe Drugs to Predict the Metabolic Capacity of CYP2A6 Due to Genetic Polymorphism in Thais

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著者

    • KIYOTANI Kazuma
    • Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University
    • FUJIEDA Masaki
    • Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University
    • YAMAZAKI Hiroshi
    • Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University
    • KAMATAKI Tetsuya
    • Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University

抄録

  The association between the distribution characteristics of CYP2A6 catalytic activities toward nicotine and coumarin, and the frequency distribution of <i>CYP2A6</i> variant alleles reported was estimated in 120 healthy Thais. The distributions of the subjects as classified by the amounts of 7-hydroxycoumarin (7-OHC) excreted in the urine and by cotinine/nicotine ratio in the plasma were clearly bimodal. However, the numbers of apparently poor metabolizers for coumarin and nicotine were different. The inter-individual variability in the <i>in vivo</i> dispositions of coumarin and nicotine closely related to the <i>CYP2A6</i> genetic polymorphism. There was a close correlation between the rate of 7-OHC excretion in the urine and cotinine/nicotine ratio in the plasma among subjects (R=0.92, p<0.001). The frequency of <i>CYP2A6</i> allele found in the present study was: <i>CYP2A6*1A</i>=32% (95% CI, 22.1-39.4%), <i>CYP2A6*1B</i>=27% (95% CI, 19.4-33.5%), <i>CYP2A6*9</i>=20% (95% CI, 17.6-23.3%), <i>CYP2A6*4</i>=14% (95% CI, 9.6-17.8%), <i>CYP2A6*7</i>=5% (95% CI, 3.7-9.4%), <i>CYP2A6*10</i>=2% (95% CI, 0.8-5.1%). Subjects having <i>CYP2A6*1A/*1B</i> were found to have a higher rate of 7-OHC excretion, as well as a higher cotinine/nicotine ratio in the plasma compared with those of the other genotypes. In contrast, subjects with <i>CYP2A6*4/*7</i> and <i>CYP2A6*7/*7</i> almost lacked any cotinine formation, whereas urinary 7-OHC was still detectable. <i>CYP2A6*9</i> allele clearly resulted in reduced enzyme activities. Despite the absence of the homozygote for <i>CYP2A6*10</i> allele, the presence of <i>CYP2A6*10</i> allele significantly decreased the enzyme activities. The results of the present study demonstrate that <i>in vivo</i> phenotyping of CYP2A6 using nicotine and coumarin are not metabolically equivalent. Nicotine is a better probe according to its specificity, while coumarin is still valuable to be used for a routine CYP2A6 phenotyping since the test employs a non-invasive method.<br>

収録刊行物

  • Drug metabolism and pharmacokinetics  

    Drug metabolism and pharmacokinetics 21(6), 475-484, 2006-12-25 

    The Japanese Society for the Study of Xenobiotics

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各種コード

  • NII論文ID(NAID)
    10018658956
  • NII書誌ID(NCID)
    AA1162652X
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    13474367
  • データ提供元
    CJP書誌  CJP引用  J-STAGE 
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