甲氧氯普胺的临床反应和副作用：与临床、人口统计学和药物遗传学参数的关联。
Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters.
机构信息
Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
出版信息
J Clin Gastroenterol. 2012 Jul;46(6):494-503. doi: 10.1097/MCG.0b013e3182522624.
OBJECTIVES
Metoclopramide is associated with variable efficacy and side effects when used in the treatment of gastroparesis.
AIM
To determine associations of clinical and pharmacogenetic parameters with response and side effects to metoclopramide in patients with upper gastrointestinal symptoms suggestive of gastroparesis.
METHODS
Gastroparetic patients treated with metoclopramide were enrolled. Clinical parameters recorded were age, sex, weight, diabetic status, gastric emptying result, daily dose, effectiveness, and side effects. DNA was isolated from salivary samples; 20 single nucleotide polymorphisms were genotyped in 8 candidate genes (ABCB1, ADRA1D, CYP1A2, CYP2D6, DRD2, DRD3, HTR4, KCNH2).
RESULTS
One hundred gastroparetic patients treated with metoclopramide participated. Dose averaged 33±16 mg/d for 1.1±1.7 years. Responders (53 of 100 patients) were older (48±15 vs. 38±11 y; P=0.0004) and heavier (body mass index of 28±7 vs. 25±7; P=0.0125). Efficacy was associated with polymorphisms in KCNH2 (rs1805123, P=0.020) and ADRA1D (rs2236554, P=0.035) genes. Side effects, occurred in 64 patients, were more common in females (83% vs. 64%; P=0.037), nondiabetics (77% vs. 47%; P=0.004), and patients with normal gastric emptying (41% vs. 17%; P=0.015). Side effects were associated with polymorphisms in CYP2D6 (rs1080985, P=0.045; rs16947, P=0.008; rs3892097, P=0.049), KCNH2 (rs3815459, P=0.015), and serotonin 5-HT4 receptor HTR4 gene (rs9325104, P=0.026).
CONCLUSIONS
Side effects to metoclopramide were more common in nondiabetic patients with normal gastric emptying. Polymorphisms in CYP2D6, KCNH2, and 5-HT4 receptor HTR4 genes were associated with side effects, whereas polymorphisms in KCNH2 and ADRA1D genes were associated with clinical response. Clinical parameters and pharmacogenetic testing may be useful in identifying patients before treatment with metoclopramide to enhance efficacy and minimize side effects.
目的
甲氧氯普胺在治疗胃轻瘫时疗效和副作用差异较大。
目的
确定临床和药物遗传学参数与上消化道症状提示胃轻瘫的患者使用甲氧氯普胺的反应和副作用之间的关系。
方法
纳入接受甲氧氯普胺治疗的胃轻瘫患者。记录的临床参数包括年龄、性别、体重、糖尿病状态、胃排空结果、日剂量、疗效和副作用。从唾液样本中提取 DNA；对 8 个候选基因（ABCB1、ADRA1D、CYP1A2、CYP2D6、DRD2、DRD3、HTR4、KCNH2）中的 20 个单核苷酸多态性进行基因分型。
结果
100 例接受甲氧氯普胺治疗的胃轻瘫患者参与了该项研究。平均剂量为 33±16mg/d，治疗时长为 1.1±1.7 年。有效组（100 例患者中的 53 例）年龄更大（48±15 岁 vs. 38±11 岁；P=0.0004），体重指数更高（28±7 公斤/平方米 vs. 25±7 公斤/平方米；P=0.0125）。疗效与 KCNH2（rs1805123，P=0.020）和 ADRA1D（rs2236554，P=0.035）基因的多态性相关。
副作用发生在 64 例患者中，女性（83% vs. 64%；P=0.037）、非糖尿病患者（77% vs. 47%；P=0.004）和胃排空正常的患者（41% vs. 17%；P=0.015）中更常见。副作用与 CYP2D6（rs1080985，P=0.045；rs16947，P=0.008；rs3892097，P=0.049）、KCNH2（rs3815459，P=0.015）和 5-羟色胺 5-HT4 受体 HTR4 基因（rs9325104，P=0.026）的多态性相关。
结论
在胃排空正常的非糖尿病患者中，甲氧氯普胺的副作用更为常见。CYP2D6、KCNH2 和 5-HT4 受体 HTR4 基因的多态性与副作用相关，而 KCNH2 和 ADRA1D 基因的多态性与临床反应相关。临床参数和药物遗传学检测可在使用甲氧氯普胺治疗之前识别患者，以提高疗效并最大程度减少副作用。
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