Nazir Shabnam, Iqbal Zafar, Ahmad Lateef, Ahmad Sagheer
Kohat University of Science and Technology, Department of Pharmacy, Kohat, Pakistan.
University of Peshawar, Peshawar, Department of Pharmacy, Peshawar, Pakistan.
Pak J Pharm Sci. 2016 May;29(3):887-94.
Pharmacokinetics (PK) variation of drugs in males and females may affect therapeutic effectiveness and safety. In current study the PK differences for omeprazole and its metabolites5-hydroxy-omeprazole and omeprazole-sulphone were evaluated in males and females. The current study also considered PK comparison of Pakistani subjects using the CYP2C19 genotype as variable. A single oral dose (40mg omeprazole), open-labeland, non-controlled clinical trial was arranged. Samples were quantified using reversed phase HPLC-UV method. CYP2C19 genotype of subjects was determined by tetra primer polymerization chain reaction (PCR) assay. There was a significant increase in Cmax (from 2 to 2.9μg/ml, p=0.004**), (from 6.67 to 8.74μg-hr/ml, p=0.05*) and elimination half-life (from 1.05 to 2.1 hr, p=0.0001*) of omeprazole in females compared with males. Cmax and of 5-hydroxy-omeprazole (0.0248* and 0.0001***, respectively) and omeprazole-sulphone (0.0001*** and 0.001**, respectively) was significantly higher in females than males when compared at 95% confidence interval. The Cmax and AUC of omeprazole showed a significant raise (p=0.01* and 0.04*, respectively) in Homz PMs (Homozygous Poor Metabolizers) compared with Homz EMs (Homozygous Extensive Metabolizers) and Htrz PMs (Heterozygous Poor Metabolizers) while Cmax and AUC of 5-hydroxy-omeprazolewas significantly higher (p=0.01* and 0.04*, respectively) in Homz EMs compared with Homz PMs and HtrzPMs. AUC of omeprazole was significantly higher in females while its elimination also took longer compared with males. AUC of omeprazole was significantly higher in Homz PMs indicating that CYP2C19* displayed genetically deficient metabolism in its homozygous state.
药物在男性和女性体内的药代动力学（PK）差异可能会影响治疗效果和安全性。在本研究中，评估了奥美拉唑及其代谢产物5-羟基奥美拉唑和奥美拉唑砜在男性和女性体内的PK差异。本研究还以CYP2C19基因型为变量，对巴基斯坦受试者的PK进行了比较。安排了一项单剂量口服（40mg奥美拉唑）、开放标签且非对照的临床试验。使用反相高效液相色谱-紫外检测法对样本进行定量。通过四引物聚合酶链反应（PCR）检测法确定受试者的CYP2C19基因型。与男性相比，女性体内奥美拉唑的Cmax（从2μg/ml增至2.9μg/ml，p=0.004**）、AUC（从6.67μg·hr/ml增至8.74μg·hr/ml，p=0.05*）和消除半衰期（从1.05小时增至2.1小时，p=0.0001*）均显著增加。在95%置信区间下比较时，女性体内5-羟基奥美拉唑的Cmax（分别为0.0248和0.0001）和奥美拉唑砜的Cmax（分别为0.0001和0.001）均显著高于男性。与纯合子广泛代谢者（Homz EMs）和杂合子代谢不良者（Htrz PMs）相比，纯合子代谢不良者（Homz PMs）体内奥美拉唑的Cmax和AUC显著升高（分别为p=0.01和0.04*），而与Homz PMs和Htrz PMs相比，Homz EMs体内5-羟基奥美拉唑的Cmax和AUC显著更高（分别为p=0.01和0.04）。与男性相比，女性体内奥美拉唑的AUC显著更高，其消除时间也更长。Homz PMs体内奥美拉唑的AUC显著更高，表明CYP2C19*在其纯合状态下表现出基因缺陷性代谢。
