Metoclopramide

Metoclopramide (brand name Reglan) is an antiemetic medication commonly used to prevent nausea and vomiting associated with chemotherapy, radiation therapy, and postoperative recovery.

It is also prescribed to treat gastroparesis by accelerating gastric emptying and relieving symptoms such as bloating, early satiety, and abdominal discomfort.

Metoclopramide works as a dopamine D2 receptor antagonist in both the central nervous system and gastrointestinal tract, enhancing lower esophageal sphincter tone, increasing peristalsis, and blocking vomiting signals in the brain.

The primary gene involved in metoclopramide metabolism is CYP2D6, a liver enzyme responsible for converting many medications into more water-soluble compounds for elimination. Variations in the CYP2D6 gene define metabolizer categories—poor, intermediate, normal, and ultrarapid—that reflect the speed at which a person processes the drug.

In simple terms, a “metabolizer” describes how active the enzyme is based on genetic variants. Poor metabolizers have reduced or no CYP2D6 function, leading to slower drug clearance, while ultrarapid metabolizers have multiple active copies, leading to faster clearance. These differences can affect drug levels, efficacy, and risk of side effects.

Genetic variations in CYP2D6 result in distinct metabolizer phenotypes that influence metoclopramide exposure: ultrarapid metabolizers clear the drug more quickly, potentially reducing effectiveness, whereas poor metabolizers clear it more slowly, increasing systemic concentrations and risk of adverse effects.

Ultrarapid Metabolizer

• Effect on drug levels: Lower than expected plasma concentrations.
• Clinical consequence: Possible reduced effectiveness for nausea control.
• Side effects: Lower risk of typical side effects (e.g., sedation), generally mild and infrequent.

Normal Metabolizer

• Effect on drug levels: Expected plasma concentrations with standard dosing.
• Clinical consequence: Standard efficacy and safety profile.
• Side effects: Expect typical side effects such as fatigue or mild sedation at normal frequency.

Intermediate Metabolizer

• Effect on drug levels: Slightly higher plasma concentrations than normal.
• Clinical consequence: Potential for increased effects and mild side effects.
• Side effects: Slightly elevated risk of sedation or mild extrapyramidal symptoms (occasional, low severity).

Poor Metabolizer

• Effect on drug levels: Higher than expected plasma concentrations.
• Clinical consequence: Increased risk of adverse effects due to accumulation.
• Side effects: Higher incidence of extrapyramidal symptoms (e.g., dystonia), sedation; severity can be moderate.

Indeterminate/Not available

• Effect on drug levels: Unknown.
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
• Side effects: Uncertain; monitor for typical reactions like sedation or movement disorders.

CYP2D6 Dosing Guideline

The FDA guideline did not list specific alternative treatments for CYP2D6 poor metabolizers. Clinicians may consider other antiemetic agents such as ondansetron or promethazine based on patient-specific factors and clinical judgment.

• FDA – Table of Pharmacogenetic Associations