Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and Safety of Sertraline in Healthy Volunteers
Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and Safety of Sertraline in Healthy Volunteers
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DOI：
10.1111/bcpt.12938
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发表时间：
2018-05-01
影响因子：
3.1
通讯作者：
Abad-Santos, Francisco
中科院分区：
文献类型：
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作者：
Saiz-Rodriguez, Miriam;Belmonte, Carmen;Abad-Santos, Francisco
舍曲林是一种选择性5-羟色胺再摄取抑制剂，在肝脏中通过细胞色素P450（CYP）酶广泛代谢。此外，它还是一种P-糖蛋白底物。此外，5-羟色胺转运体和5-羟色胺受体参与其功效和安全性。本研究的目的是评价代谢酶、转运体和受体的多态性对舍曲林在健康志愿者体内的药代动力学、药效学和耐受性的作用。46名健康志愿者对接受100 mg单次口服舍曲林的24名男性和22名女性患者进行了17种β-内酰胺酶遗传变异的基因分型（CYP 2B 6、CYP 2C 9、CYP 2C 19、CYP 2D 6）、ATP结合盒亚家族B成员1（ABCB 1）、溶质载体家族6成员4（SLC 6A 4），5-羟色胺受体2A（HTR 2A）和5-羟色胺受体2C（HTR 2C）基因。男性和女性的药代动力学和药效学参数相似。CYP 2C 19和CYP 2B 6基因多态性影响舍曲林的药代动力学，CYP 2C 19的影响更大。携带CYP 2C 19和CYP 2B 6缺陷等位基因的个体显示出更高的曲线下面积（AUC）和半衰期（T-1/2）。此外，CYP 2C 19 *17与AUC和T-1/2降低相关。CYP 2C 9、CYP 2D 6和ABCB 1基因多态性对舍曲林药代动力学无显著影响。舍曲林有一个小的心率降低作用，直接相关的最大浓度（C-max）和ABCB 1次要等位基因的存在。舍曲林对血压和QTc无明显影响。在女性和舍曲林AUC较高的个体中，如CYP 2C 19中间代谢型和CYP 2B 6 G516 T/T个体，有出现更多药物不良反应的趋势。
Sertraline is a selective serotonin reuptake inhibitor widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P-glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of this study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty-six healthy volunteers (24 men and 22 women) receiving a 100-mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP-binding cassette subfamily B member 1 (ABCB1), solute carrier family 6 member 4 (SLC6A4), 5-hydroxytryptamine receptor 2A (HTR2A) and 5-hydroxytryptamine receptor 2C (HTR2C) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP2C19 and CYP2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP2C19. Individuals carrying defective alleles for CYP2C19 and CYP2B6 showed higher area under the curve (AUC) and half-life (T-1/2). Moreover, CYP2C19*17 was related to a decreased AUC and T-1/2. No significant effect was found for polymorphisms in CYP2C9, CYP2D6 and ABCB1 on sertraline pharmacokinetics. Sertraline had a small heart rate-lowering effect, directly related to maximum concentration (C-max) and the presence of ABCB1 minor alleles. Sertraline had no significant effect on blood pressure and QTc. There was a tendency to present more adverse drug reactions in women and individuals with higher AUC of sertraline, such as CYP2C19 intermediate metabolizers and CYP2B6 G516T T/T individuals.