著者

斉藤 嘉津彦 清水 瓊子 岡崎 正子 伊林 至洋 端 和夫 前野 康次郎 石井 清二 土橋 和文 島本 和明 戸田 貴大 黒澤 菜穂子 大和田 栄治 加藤 芳伸 大山 徹 梅津 有理 千田 道洋 有吉 範高 鎌滝 哲也 板谷 幸一

出版者

一般社団法人日本医療薬学会

雑誌

医療薬学 (ISSN:1346342X)

巻号頁・発行日

vol.27, no.3, pp.228-234, 2001-06-10 (Released:2011-03-04)

参考文献数

11

被引用文献数

1 1

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In recent years, genome science has undergone radical changes and numerous advances have led to the development of its use in medical practice. In particular developments in pharmacogenetics have demonstrated that genetic polymorphism is responsible for inter-individual differences in the drug metabolism. This study was conducted to identify the genetic polymorphisms of CYP 2C 9 and CYP 2 C19 using PCR-RFLP, and the application of a gene analysis was investigated in TDM or pharmaceutical management and in counseling services for patients. In a patient with the following pharmacokinetic parameters for phenytoin, for Km=6.69 μg/mL and Vmax = 3.62 mg/day/kg, and a largely decreased metabolic activity of CYP 2 C9 compared to the general population, the genetic differences in CYP 2 C9 could be determined in genomic DNA based on the patient's peripheral blood. Based on this finding, the effective dose for medication was calculated and administered to the patient. In addition, during medical consultations, both written and oral information in an easily comprehensible form could be given to patients with genetic polymorphism. These procedures allow a for the careful matching of the patient to the right medication and dose. This study indicates the possible application of a genetic analysis of CYP to “Evidence-Based Medicine” in the field of pharmaceutical management in order to control the dosage in individuals and to improve patient counseling.

著者

有吉 範高 布谷 憲一 高橋 由紀 宮本 昌美 醍醐 聡 梅津 有理 横井 毅 木村 寛三 Philippe BEAUNE 鎌滝 哲也

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.15, no.1, pp.57-61, 2000 (Released:2007-03-29)

参考文献数

28

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CYP2A6 has been characterized as a coumarin 7-hydroxylase in humans. A large interindividual difference in the activity of coumarin 7-hydroxylation suggested an existence of genetic polymorphism of this enzyme. In fact, CYP2A6*2 variant allele which has T→A substitution, leading to amino acid change from Leu160 to His160, has been found in Caucasian population as the most frequent mutation in poor metabolizers (PM) of coumarin. Although several drugs used clinically or under development such as fadrozole, losigamone and methoxyflurane are recognized at present to be good substrates of CYP2A6, no specific substrate of this CYP isoform has been known until we found a drug, SM-12502. In the phase I trial, 3 out of 28 Japanese subjects were classified as PM of the drug. In vitro studies demonstrated that CYP2A6 played a major role on the metabolism of the drug. Genomic analysis revealed that the PM phenotype was caused by the presence of a novel CYP2A6 gene variant which lacks the entire region of open reading frame encoding the enzyme in the PM. Thus, we designated the variant as “deletion-type” allele. We examined the frequency of individuals carrying homozygous deletion by a genotyping method established in our laboratory. Thus, the frequency was estimated to be 3-4% in Japanese. We found another CYP2A6 gene variant whose 60 bp in the 3'-untranslated region was substituted by the corresponding region of the CYP2A7 pseudogene. This variant was designated as “conversion-type” allele. We found that the allele frequency of the conversiontype was comparable to that of wild-type, CYP2A6*1 allele in Japanese. We also compared the frequency of the CYP2A6*2 allele as well as the deletion and the conversion alleles between Japanese and Caucasian. Consequently, a marked interracial difference in the frequency of the genetic variants of the CYP2A6 gene was observed. These results give an interesting insight into racial difference in response to drugs and evolution of the CYP2A gene subfamily in humans.