Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans
Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans
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DOI：
10.1177/0091270002239710
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发表时间：
2003-01-01
影响因子：
2.9
通讯作者：
Goldstein, JA
中科院分区：
文献类型：
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作者：
Lee, CR;Pieper, JA;Goldstein, JA
对16例表达4种不同基因(*1/*1、*1/*2、*1/*3和*2/2)的受试者的代谢活性进行了研究。采用随机交叉设计，单剂量口服甲苯丁胺、氟比洛芬和氯沙坦。24小时内采集血浆和尿液。尿代谢率和代谢物(S)排泄量与产后排泄率相关。与氟比洛芬和洛沙顿相比，甲苯丁胺对其CYP2C9介导的代谢物的形成清除率与基因型的相关性更强(r(2)=0.64比0.53比0.42)。甲苯磺丁胺的形成清除量与4‘-羟基甲苯丁胺和羧基甲苯丁胺0~12小时的尿量呈显著正相关(r=0.84)。与甲苯磺丁胺相比，氟比洛芬和氯沙坦代谢指标之间的相关性不是很强。甲苯丁胺是一种比氟比洛芬和氯沙坦更好的CYP2C9探针，而0到12小时的4‘-羟基甲苯丁胺和羧基甲苯丁胺是衡量其代谢的最佳尿液指标。
The metabolic activity of CYP2C9 in 16 subjects expressing four different genotypes (CYP2C9*1/*1, *1/*2, *1/*3, and *2/*2) was evaluated. Single oral doses of tolbutamide, flurbiprofen, and losartan were administered in a randomized, crossover design. Plasma and urine were collected over 24 hours. The urinary metabolic ratio and amount of metabolite(s) excreted were correlated with formation clearance. The formation clearance of tolbutamide to its CYP2C9-mediated metabolites demonstrated a stronger association with genotype compared to flurbiprofen and losarton, respectively (r(2) = 0.64 vs. 0.53 vs. 0.42). A statistically significant correlation was observed between formation clearance of tolbutamide and the 0- to 12-hour urinary amount of 4'-hydroxy-tolbutamide and carboxytolbutamide (r = 0.84). Compared to tolbutamide, the correlations observed between the respective measures of flurbiprofen and losartan metabolism were not as strong. Tolbutamide is a better CYP2C9 probe than flurbiprofen and losartan, and the 0- to 12-hour amount of 4'-hydroxytolbutomide and carboxytolbutamide is the best urinary measure of its metabolism.