Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects
Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects
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DOI：
10.1007/s00228-003-0664-5
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发表时间：
2003-11-01
影响因子：
2.9
通讯作者：
Iga, T
中科院分区：
文献类型：
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作者：
Sekino, K;Kubota, T;Iga, T
目的：氯沙坦通过CYP 2C 9代谢为活性羧酸代谢产物EXP 3174。在这项研究中，我们确定的影响，单CYP 2C 9 *3变异的药代动力学和药效学的losartan.Methods：7个健康的日本受试者（CYP 2C 9 *1/*1，n = 4和CYP 2C 9 *1/*3，n = 3）的表型与单剂量的氯沙坦（25 mg）。采集血液和尿液样本，并测定氯沙坦和EXP 3174。结果：CYP 2C 9 *1/*3（n = 3）组的EXP 3174最大血药浓度显著低于CYP 2C 9 *1/*1（n = 4）组（P < 0.05）。与基线水平相比，CYP 2C 9 *1/ *1组的舒张压从1.5 h降至12 h，但CYP 2C 9 *1/*3组的舒张压除外（6 It和8 h）。与基线水平相比，CYP 2C 9 *1/*1组的收缩压从1小时降低至12小时，而CYP 2C 9 *1/*3组的收缩压未降低。CYP 2C 9 *1/*3组给药后6 h血浆中EXP 3174浓度与氯沙坦浓度的代谢比（MR）和4 h至8 h尿EXP 3174/氯沙坦MR显著低于CYP 2C 9 *1/*1组。血浆6 h MR和4 h ~ 8 h尿MR与血浆AUC比值（AUC（EXP 3174）/AUC（losartan））显著相关（P < 0.05），斯皮尔曼秩相关系数分别为0.75和0.89。血浆MR和尿液MR可能有助于CYP 2C 9活性的表型分析。
Objective: Losartan is metabolized to the active carboxylic acid metabolite EXP3174 by CYP2C9. In this study, we determined the effects of the single CYP2C9*3 variant on the pharmacokinetics and pharmacodynamics of losartan.Methods: Seven healthy Japanese subjects (CYP2C9*1/*1, n = 4 and CYP2C9*1/*3, n = 3) were phenotyped with a single dose of losartan (25 mg). Blood and urine samples were collected and assayed for losartan and EXP3174. Blood pressure and pulse rate were also measured using a sphygmomanometer.Results: The maximum plasma concentration of EXP3174 was significantly (P < 0.05) lower in the CYP2C9*1/*3 (n = 3) group than in the CYP2C9*1/*1 (n = 4) group. Diastolic blood pressure in the CYP2C9*1/ *1 group, but not that in the CYP2C9*1/*3 group except for at 6 It and 8 h, was reduced from 1.5 h to 12 h compared with the baseline level. Systolic blood pressure in the CYP2C9*1/*1 group, but not that in the CYP2C9*1/*3 group, was reduced from 1 h to 12 h compared with the baseline level. The metabolic ratio (MR) of EXP3174 concentration to the losartan concentration in plasma at 6 h post-dosing and the 4-h to 8-h urinary EXP3174/losartan MR were significantly lower in the CYP2C9*1/*3 group than in the CYP2C9*1/*1 group. The plasma 6-h MR and the 4-h to 8-h urinary MR were significantly (P < 0.05) correlated with the plasma AUC ratio (AUC(EXP3174)/AUC(losartan)), with Spearman rank correlation coefficients of 0.75 and 0.89, respectively.Conclusion: The single CYP2C9*3 variant reduces the metabolism of losartan and its hypotensive effect. Plasma MR, as well as urine MR, may be useful for phenotyping assays of CYP2C9 activity.