Metoclopramide in the Treatment of Diabetic Gastroparesis

Pharmacokinetics & Metabolism

Metoclopramide undergoes first-pass hepatic metabolism and exhibits significant individual variation in metabolism. Metoclopramide is partially metabolized by the cytochrome P450 (CYP) system. It is primarily metabolized via the CYP2D6 isoform and to a lesser extent by CYP3A and CYP1A2.^[17] Oral bioavailability ranges from 30 to 100%, while approximately 20–30% of the drug is excreted unchanged in the urine.^[18] Impaired clearance of the drug is seen in cirrhosis as well as renal insufficiency.^[19,20] Interindividual differences in the genotype and phenotype of CYP2D6 may increase the risk for complications from metoclopramide, including tardive dyskinesia (TD).^[21] Moreover, metoclopramide acts not only as a substrate for CYP2D6, but also as a competitive inhibitor of the enzyme. This is similar to other neuroleptic agents, such as haloperidol, thioridazine, chlorpromazine, perphenazine and risperidone.^[22] As a result, concomitant use of metoclopramide with a neuroleptic agent may increase the bioavailability of each drug and lead to an increased risk of TD.

The vast majority (>90%) of therapeutic drugs are metabolized by CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Drug–drug interactions occur because of induction and/or inhibition of these isoforms.^[23] Patients on metoclopramide are particularly at risk for these interactions because of a likelihood of polypharmacy. Patients with gastroparesis often take medications to relieve pain and nausea, and drugs to treat comorbidities (e.g., diabetes and psychiatric illness). Medications for diabetes, such as amylin analogs (e.g., pramlintide) and GLP-1 (e.g., exenatide), have been demonstrated to cause or exacerbate delayed gastric emptying.^[24–26] Coexisting psychiatric disorders are also common and may contribute to symptoms of gastroparesis. In a cross-sectional study, depression, anxiety and neuroticism were associated with a doubling of the prevalence of gastrointestinal symptoms in diabetics.^[27] In addition, adverse drug reactions involving CYP2D6 are likely to be significant, as 30% of drugs are substrates of this enzyme, including opioids, neuroleptics, antidepressants and cardiac medications.^[28]

Cite this: Metoclopramide in the Treatment of Diabetic Gastroparesis - Medscape - Sep 01, 2010.

Table 1. Risk of tardive dyskinesia with metoclopramide.
Study (year)	Study design	Number studied	Result	Estimated prevalence	Ref.
Wilholm et al. (1984)	Scandinavian prescription database, 1977–1981	11 million Rx of metoclopramide	37 reports of EPS with 11 TD casesAll females, mean age of 76 years	One in 2000–28,000 patient-years, one in 17,800 perscriptions	^[71]
Bateman et al. (1985)	UK prescription database, 1967–1982	15.9 million Rx of metoclopramide	479 reports of EPS, four with TD	One in ~35,000 prescriptions, significantly higher risk in females, especially those 12–19 years old	^[64]
Sewell et al.(1992)	Analysis of 67 case reports of metaclopramide-induced TD	52 patients on at least 30 days of metoclopramide	Mean age of 70 ± 19 years, 3:1 female predominance and Rx duration of 20 ± 15 months; 47% TD cases persisted at 6 months despite discontinuation of metoclopramide	Not estimable	^[74]
Ganzini et al. (1993)	VA study using exposed/unexposed design, matched for age, gender, diabetes and comorbidities	51 chronic Rx of metoclopramide; 51 unexposed	Mean age of 63.9 ± 10.8 years, male predominant, duration of treatment 2.6 ± 2.0 years	29% TD in metoclopramide Rx vs 17.6% in nonusers (p = 0.08)	^[65]
Sewell et al. (1994)	VA cross-sectional study	51 patients with metoclopramide-associated TD; 35 controls matched for age, race, gender and diabetes	Duration of metoclopramide treatment of at least 30 days	27% TD in metoclopramide Rx vs 12% nonusers (p = 0.08) Patients on metoclopramide and diabetic more likely to develop TD (p = 0.05)	^[73]
Shafter et al. (2004)	International metoclopramide adverse event reports and US drug-use data	87 case reports	Mean duration of Rx of 753 ± 951 days; 37% used concomitant drugs, 18% had comorbid diseases with TD risk	Not estimableIncreased use of metoclopramide afer cisapride withdrawal	^[16]
Kenney et al. (2008)	Observational study in a tertiary-care movement-disorder clinic	434 patients referred for TD	Metoclopramide accounted for 39.4% of TD, the second-leading cause of TD after haloperidol	Not estimable	^[72]

EPS: Extrapyramidal side effects; TD: Tardive dyskinesia; VA: Veterans administration.
Adapted from ^{[14,16,64,65,71–74]}.

Box 1. Effects of metoclopramide.
Gastric motility D₂receptor antagonist Stimulation 5-HT₄receptors Muscarinic receptor antagonist Symptoms of gastroparesis Promotes gastric emptying Anti-emetic effects via central pathways Normalization of gastric slow wave dysrhythmias Modulates visceral hypersensitivity

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Metoclopramide in the Treatment of Diabetic Gastroparesis

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