Increased omeprazole metabolism in carriers of the CYP2C19*17 allele;: a pharmacokinetic study in healthy volunteers
Increased omeprazole metabolism in carriers of the CYP2C19*17 allele;: a pharmacokinetic study in healthy volunteers
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DOI：
10.1111/j.1365-2125.2008.03104.x
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发表时间：
2008-05-01
影响因子：
3.4
通讯作者：
Bertilsson, Leif
中科院分区：
文献类型：
--
作者：
Baldwin, R. Michael;Ohlsson, Staffan;Bertilsson, Leif
目的研究CYP 2C 19 *17等位基因对奥美拉唑（一种常用的CYP 2C 19探针药物）在健康志愿者体内药代动力学的影响.方法在一项单剂量药代动力学研究中，17名基因型为CYP 2C 19 *17/*17或CYP 2C 19 *1/*1的健康白色志愿者接受40 mg奥美拉唑口服给药。给药后10小时内采集血浆样品，然后通过高效液相色谱法定量奥美拉唑、5-羟基奥美拉唑和奥美拉唑砜。在CYP 2C 19 *17/*17受试者中，1973 h nmol l（-1）（无穷大）降低了2.1倍[95%置信区间（CI）1.1，CYP 2C 19 *1/*1受试者中的平均值为4151 h nmol l（-1），P = 0.04。砜代谢物也观察到类似趋势，CYP 2C 19 *17/*17组的平均AUC（无穷大）为1083 h nmol l（-1），比CYP 2C 19 *1/*1组（3343 h nmol l（-1），P = 0.03）低3.1倍（95% CI 1.2，5.5）。在个体内奥美拉唑AUC（无穷大）和奥美拉唑砜AUC（无穷大）值中观察到明显的相关性（r（2）= 0.95，P < 0.0001）。对于主要由CYP 2C 19代谢的临床重要药物，CYP 2C 19 *17等位基因可能与亚治疗药物暴露相关。
AIMSTo investigate the influence of the CYP2C19*17 allele on the pharmacokinetics of omeprazole, a commonly used CYP2C19 probe drug, in healthy volunteers.METHODSIn a single-dose pharmacokinetic study, 17 healthy White volunteers genotyped as either CYP2C19*17/*17 or CYP2C19*1/*1 received an oral dose of 40 mg of omeprazole. Plasma was sampled for up to 10 h postdose, followed by quantification of omeprazole, 5-hydroxy omeprazole and omeprazole sulphone by high-performance liquid chromatography.RESULTSThe mean omeprazole AUC(infinity) of 1973 h nmol l(-1) in CYP2C19*17/*17 subjects was 2.1-fold lower [95% confidence interval (CI) 1.1, 3.3] than in CYP2C19*1/*1 subjects (4151 h nmol l(-1), P = 0.04). A similar trend was observed for the sulphone metabolite with the CYP2C19*17/*17 group having a mean AUC(infinity) of 1083 h nmol l(-1), 3.1-fold lower (95% CI 1.2, 5.5) than the CYP2C19*1/*1 group (3343 h nmol l(-1), P = 0.03). A pronounced correlation (r(2) = 0.95, P < 0.0001) was seen in the intraindividual omeprazole AUC(infinity) and omeprazole sulphone AUC(infinity) values.CONCLUSIONSThe pharmacokinetics of omeprazole and omeprazole sulphone differ significantly between homozygous CYP2C19*17 and CYP2C19*1 subjects. For clinically important drugs that are metabolized predominantly by CYP2C19, the CYP2C19*17 allele might be associated with subtherapeutic drug exposure.