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

目的1：我们确定咖啡因和苯妥英这两种探针药物是否可以同时作为鸡尾酒试验来评估体内三种细胞色素P450 (CYP1A2, 2C9和2C19)， n-乙酰转移酶（NAT2），黄嘌呤氧化酶（XO）和含黄素单加氧酶（FMO）酶的活性。在1999年。方法：29名健康志愿者（男性14名，女性15名）分别口服150毫克咖啡因和100毫克苯妥英，并使用3 × 3拉丁方格联合服用。CYP1A2、NAT2和XO的活性通过尿咖啡因代谢率表达，CYP2C9和2C19的活性通过苯酞英手性代谢率表达。结果：确定了咖啡因的分离表型和混合表型具有相关性，而苯妥英的分离表型和混合表型没有相关性。Aim #2：在Aim #1的基础上，于2000年在日本九州扩展了咖啡因表型试验，以评估CYP1A2、NAT2、XO、FMO和CYP2A6五种药物代谢酶的体内活性。方法：282名健康志愿者（男性108人，女性74人）在睡前口服150 mg咖啡因，采集夜间尿液样本，用高效液相色谱法分析咖啡因及其代谢物的浓度。酶活性通过尿咖啡因代谢率表达。结果：CYP1A2、FMO和CYP2A6活性的频率分布为单峰，而NAT2和XO活性的频率分布分别为三峰和双峰。吸烟者CYP1A2活性高于非吸烟者（p<0.0001）。缓慢乙酰化发生率为11%。CYP1A2、XO活性在雄鼠中显著高于雌鼠（p<0.01）， NAT2活性显著低于雌鼠（p<0.02）。少数受试者CYP1A2、XO、FMO和CYP2A6的活性明显降低。我们目前正在确定这些酶的基因型，并将确定其治疗相关性。

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.