A POPULATION PHENOTYPING STUDY ON SIX (FIVE) DRUG-METABOLIZING ENZYMES AND THE THERAPEUTIC RELEVANCE.

关于六（五）种药物代谢酶及其治疗相关性的群体表型研究。

基本信息

批准号：
11672267
负责人：
ISHIZAKI Takashi
金额：
$ 2.3万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Aim #1 : We determined whether the two probe drugs, caffeine and phenytoin, could be simultaneously administered as a cocktail test to estimate three cytochromes P450 (CYP1A2, 2C9 and 2C19), N-acetyltransferase (NAT2), xanthine oxidase (XO) and flavin-containing monooxygenase (FMO) enzyme activities in vivo. in 1999.Methods : Twenty-nine healthy volunteers (14 men and 15 women) received orally 150 mg of caffeine and 100 mg of phenytoin separately and in combination using a 3x3 Latin square. The activities of CYP1A2, NAT2 and XO were expressed by urinary caffeine metabolic ratios, and those of CYP2C9 and 2C19 by phenytoin chiral metabolite ratios.Results : Ascertaining the separate and cocktail phenotyping tests for caffeine correlated with each other, but that for phenytoin did not.Aim #2 : Based on the results of Aim #1, caffeine phenotyping test was extended to assess in vivo activities of five drug-metabolizing enzymes, CYP1A2, NAT2, XO, FMO and CYP2A6 in Kyushu, Japan, in 2000.Methods : One hundred eighty-two healthy volunteers (108 men and 74 women) received an oral 150-mg dose of caffeine before sleep, then overnight urine sample was collected and the concentrations of caffeine and its metabolites were analyzed by HPLC.The enzyme activities were expressed by urinary caffeine metabolic ratios.Results : Frequency distributions of CYP1A2, FMO, and CYP2A6 activities were unimodal, whereas those of NAT2, and XO activities were trimodal and bimodal, respectively. The CYP1A2 activity was statistically higher in smokers than in non-smokers (p<0.0001). The frequency of slow acetylators was 11%. The activities of CYP1A2 and XO were statistically higher (p<0.01), and that of NAT2 was lower (p<0.02) in males than in females. A few subjects showed significantly low activities of CYP1A2, XO, FMO, and CYP2A6. We are currently determining the genotypes of these enzymes and will determine the therapeutic relevance.

Aim #1 : We determined whether the two probe drugs, caffeine and phenytoin, could be simultaneously administered as a cocktail test to estimate three cytochromes P450 (CYP1A2, 2C9 and 2C19), N-acetyltransferase (NAT2), xanthine oxidase (XO) and flavin-containing monooxygenase (FMO) enzyme activities体内。 1999年。方法：29名健康志愿者（14名男性和15名女性）分别接受150毫克咖啡因和100毫克的苯妥英钠，并使用3x3拉丁正方形进行组合。 The activities of CYP1A2, NAT2 and XO were expressed by urinary caffeine metabolic ratios, and those of CYP2C9 and 2C19 by phenytoin chiral metabolite ratios.Results : Ascertaining the separate and cocktail phenotyping tests for caffeine correlated with each other, but that for phenytoin did not.Aim #2 : Based on the results of Aim #1, caffeine phenotyping test was extended to assess in vivo activities of five drug-metabolizing enzymes, CYP1A2, NAT2, XO, FMO and CYP2A6 in Kyushu, Japan, in 2000.Methods : One hundred eighty-two healthy volunteers (108 men and 74 women) received an oral 150-mg dose of caffeine before sleep, then overnight urine sample was collected and the通过HPLC分析咖啡因及其代谢产物的浓度。酶活性通过尿咖啡因代谢比表达。分子：CYP1A2，FMO和CYP2A6活性的频率分布是单模型的，而Nat2和XO活动的频率分布是Trimodal和Bimodal的频率分布。吸烟者的CYP1A2活性在统计学上高于非吸烟者（p <0.0001）。缓慢的乙酰剂的频率为11％。 CYP1A2和XO的活性在统计学上更高（p <0.01），而男性的Nat2的活性比女性低（p <0.02）。一些受试者的CYP1A2，XO，FMO和CYP2A6的活性显着较低。我们目前正在确定这些酶的基因型，并将确定治疗性相关性。