Clinical Response and Side Effects of Metoclopramide Associations With Clinical, Demographic, and Pharmacogenetic Parameters

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.