Domperidone treatment for gastroparesis: demographic and pharmacogenetic characterization of clinical efficacy and side-effects.
BACKGROUND
Domperidone is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability. Effectiveness and side-effects from domperidone may be influenced by patient-related factors including polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, and domperidone targets.


OBJECTIVE
The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side-effects.


METHODS
Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted. Fourteen single-nucleotide polymorphisms (SNPs) in seven candidate genes (ABCB1, CYP2D6, DRD2, KCNE1, KCNE2, KCNH2, KCNQ1) were used for genotyping. SNP microarrays were used to assess single-nucleotide polymorphisms in the ADRA1A, ADRA1B, and ADRA1D loci.


RESULTS
Forty-eight patients treated with domperidone participated in the study. DNA was successfully obtained from each patient. Age was associated with effectiveness of domperidone (p=0.0088). Genetic polymorphism in KCNH2 was associated with effectiveness of domperidone (p=0.041). The efficacious dose was associated with polymorphism in ABCB1 gene (p=0.0277). The side-effects of domperidone were significantly associated with the SNPs in the promoter region of ADRA1D gene.


CONCLUSIONS
Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene ABCB1, the potassium channel KCNH2 gene, and α1D--adrenoceptor ADRA1D gene. Age was associated with a beneficial response to domperidone. If verified in a larger population, this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side-effects.
Gastroenterology Section, School of Medicine, Temple University School of Medicine, Parkinson Pavilion, 8th floor, 3401 North Broad Street, Philadelphia, PA 19140, USA. henry.parkman@temple.edu
Henry P
HP
Parkman
Michael R
MR
Jacobs
Anurag
A
Mishra
Jessica A
JA
Hurdle
Priyanka
P
Sachdeva
John P
JP
Gaughan
Evgeny
E
Krynetskiy
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000932:Antiemetics / Q000009:adverse effects* / Q000627:therapeutic use*; D004294:Domperidone / Q000009:adverse effects* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D018589:Gastroparesis / Q000188:drug therapy* / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics; D016896:Treatment Outcome
C513055:ABCB1 protein, human; C547719:ADRA1D protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000932:Antiemetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D018340:Receptors, Adrenergic, alpha-1; D004294:Domperidone