Department of Pharmacology, Pharmacogenomic Research Center for Membrane Transporters, Brain Korea 21 Project for Medical Science, Seoul, Korea.
J Clin Psychopharmacol. 2013 Aug;33(4):491-8. doi: 10.1097/JCP.0b013e3182905a8d.
Osmotic-release oral system (OROS)-methylphenidate (MPH) is a safe and well-tolerated drug. Some patients cannot continue this regimen with adverse drug reactions (ADRs). As drug efflux transporters of the central nervous system, ABCB1 plays an important role in the clearance of psychotropic drugs and their metabolites from brain tissues. We hypothesized that genetic variations in the ABCB1 gene may affect ADRs to OROS-MPH.
We analyzed ADRs of OROS-MPH in 134 children and adolescents with attention-deficit hyperactivity disorder who completed a 4-week trial of OROS-MPH. The ADRs of OROS-MPH were evaluated by administering the Barkley Stimulant Side Effects Rating Scale.
Our study proved that MPH is a substrate for ABCB1 by using membrane vesicle assay. We analyzed the influence of ABCB1 polymorphisms on ADRs to OROS-MPH. From the association study between ABCB1 polymorphisms and ADRs of OROS-MPH, c.2677G>T (p.Ala893Ser, rs2032582) showed a strong association with OROS-MPH-related ADRs (P = 0.008; odds ratio, 5.72). Furthermore, logistic regression analysis indicated that the TT genotype at the ABCB1 2677 locus is an independent determinant of ADRs attributed to OROS-MPH. In a functional study, the 893Ser variant markedly reduced MPH transport across the cell membrane.
This is the first study to demonstrate that the TT genotype at position 2677 in the ABCB1 gene is associated with ADRs to OROS-MPH.
渗透释放口腔系统（OROS）-哌甲酯（MPH）是一种安全且耐受良好的药物。一些患者由于不良反应（ADR）而无法继续使用该方案。作为中枢神经系统的药物外排转运蛋白，ABCB1 在精神药物及其代谢物从脑组织中的清除中起着重要作用。我们假设 ABCB1 基因的遗传变异可能会影响 OROS-MPH 的 ADR。
我们分析了 134 名患有注意缺陷多动障碍的儿童和青少年在接受 OROS-MPH 为期 4 周的试验期间的 OROS-MPH 的 ADR。通过 Barkley 兴奋剂副作用评定量表评估 OROS-MPH 的 ADR。
我们的研究通过膜囊泡测定证明了 MPH 是 ABCB1 的底物。我们分析了 ABCB1 多态性对 OROS-MPH 的 ADR 的影响。从 ABCB1 多态性与 OROS-MPH 的 ADR 之间的关联研究中，c.2677G>T（p.Ala893Ser，rs2032582）与 OROS-MPH 相关的 ADR 具有很强的相关性（P=0.008；优势比，5.72）。此外，逻辑回归分析表明，ABCB1 2677 位点的 TT 基因型是 OROS-MPH 相关 ADR 的独立决定因素。在功能研究中，893Ser 变体明显降低了 MPH 通过细胞膜的转运。
这是第一项表明 ABCB1 基因 2677 位的 TT 基因型与 OROS-MPH 的 ADR 相关的研究。
