2001 Fiscal Year Final Research Report Summary
Genetic analysis of CYP2D6, a drug-metabolizing enzyme for improving pharmacotherapy using evidence-based medicine principles
| Project/Area Number |
12470525
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Osaka University |
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Principal Investigator |
AZUMA Junichi Osaka Univ., Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (30144463)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Isamu Osaka Univ., Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (30281132)
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| Project Period (FY) |
2000 – 2001
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| Keywords | CYP2D6^*1 / CYP2D6^*10 / CYP2D6^*36 / Expression of CYP2D6^*cDNA / Competitive inhibition / β-blocker / CYP2D6^*5 / misjudge |
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| Research Abstract |
In Japanese subjects, we found a significant influence on the pharmacokinetics of venlafaxine by CYP2D6^*10 allele. We hypothesized that the CYP2D6^*10 allele may be a factor in determining interindividual differences in the pharmacokinetics of CYP2D6 substrates. Thus, we conducted this study from this point of view. In clinical study, mexiletine was administered orally to CYP2D6^*1 homozygous subjects and CYP2D6^*10 homozygous subjects. There was no significant difference between the two groups in pharmacokinetics data. But one subject showed higher level of plasma mexiletine concentration than other subjects. We analyzed the genetic structure of CYP2D6 of him and we concluded that it was constructed from twice tandem repeats of CYP2D6^*36. We found the frequency of this genotype was 3 %. CYP2D6.1, CYP2D6.10 and CYP2D6.36 were expressed in yeast cells and their catalytic activities for CYP2D6 substrates, bufurarol and venlafaxine were investigated. The results suggested that the decreased in vivo clearance by CYP2D6^*10 and CYP2D6^*36 was caused not only by low expression of but also increased Km value. We investigated the inhibition of CYP2D6.1, CYP2D6.10 and CYP2D6.36 by β blockers. These inhibitions were all competitive. Ki values show CYP2D6.36>>CYP2D6.10> CYP2D6.1. In patients carrying CYP2D6^*10 or CYP2D6^*36, drug-drug interactions might appear less frequently than in those carrying CYP2D6^*1. In Japanese population allelic frequency of CYP2D6^*5, which results in absence of CYP2D6 enzyme activity, is 4.5 %. It is important to detect CYP2D6^*5 genotype correctly. But we found a new genetic structure of non-CYP2D6^*5 genotype and we are apt to misjudge it as CYP2D6^*5 genotype using conventional long -PCR method for the detection of CYP2D6^*5.
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