Metoclopramide in the Treatment of Diabetic Gastroparesis

Allen Lee; Braden Kuo


Expert Rev Endocrinol Metab. 2010;5(5):653-662. 

In This Article

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]


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