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Ondansetron

Antiemetic (5-HT3 Receptor Antagonist)

Drug Overview

Ondansetron, marketed under the brand name Zofran, is a medication commonly used to prevent and treat nausea and vomiting. It belongs to the class of 5-HT3 (serotonin) receptor antagonists and is widely prescribed in oncology, radiation therapy, and postoperative settings.

This drug is approved for managing chemotherapy- and radiation-induced nausea and vomiting, as well as postoperative nausea and vomiting. By blocking serotonin signals at 5-HT3 receptors in the central nervous system and gastrointestinal tract, ondansetron helps reduce the vomiting reflex.

Ondansetron is available in oral tablet, dissolvable film, and injectable forms, allowing flexibility based on patient needs and treatment settings.

Relevant Genes and Their Roles

Ondansetron is primarily processed by the CYP2D6 enzyme in the liver. CYP2D6 is part of the cytochrome P450 family, which is responsible for metabolizing many drugs. Metabolism is the liver’s way of converting medications into forms that are easier for the body to eliminate.

Variations in the CYP2D6 gene can alter enzyme activity levels. Some people have faster-than-normal metabolism, breaking down ondansetron quickly, while others have slower metabolism, leading to prolonged drug exposure. These differences can impact both the effectiveness and side effect profile of the medication.

Impact of Genetics on Drug Response

CYP2D6 genetic variants are classified into ultrarapid, normal, intermediate, and poor metabolizers. Ultrarapid metabolizers may clear ondansetron too quickly, reducing its antiemetic effect, whereas poor metabolizers clear it more slowly, potentially increasing drug exposure. Intermediate and normal metabolizers generally show expected responses without adjustments.

Expected Clinical Effects of Genetic Variation

Ultrarapid Metabolizer

  • Effect on drug levels: Decreased plasma concentration due to faster metabolism
  • Clinical consequence: Reduced antiemetic effect; higher risk of breakthrough nausea and vomiting
  • Side effects: Fewer drug-related adverse effects; moderate frequency of nausea/vomiting

Normal Metabolizer

  • Effect on drug levels: Expected plasma concentration with standard metabolism
  • Clinical consequence: Typical antiemetic response
  • Side effects: Common side effects such as headache and constipation; mild and occasional

Intermediate Metabolizer

  • Effect on drug levels: Slightly elevated plasma levels compared to normal
  • Clinical consequence: Generally effective antiemetic response
  • Side effects: Similar to normal metabolizers; mild and infrequent

Poor Metabolizer

  • Effect on drug levels: Increased plasma concentration due to slower metabolism
  • Clinical consequence: Efficacy similar to normal metabolizers based on current evidence
  • Side effects: Potential for increased exposure side effects; mild and infrequent

Indeterminate / Not Available

  • Effect on drug levels: Unknown
  • Clinical consequence: No specific guidance; follow standard dosing with monitoring
  • Side effects: Unknown

Dosing Guidelines

The following dosing guidelines are based on recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC) for ondansetron and tropisetron and the CYP2D6 genotype.

CYP2D6 Dosing Guideline

Phenotype Clinical Consequence Guideline Recommendation
Ultrarapid Metabolizer Increased metabolism to less active compounds, leading to decreased response Select an alternative drug not predominantly metabolized by CYP2D6 (e.g., granisetron).
Normal Metabolizer Normal metabolism and expected therapeutic response Initiate therapy with the recommended starting dose.
Intermediate Metabolizer Very limited data available for CYP2D6 intermediate metabolizers Insufficient evidence demonstrating clinical impact; initiate therapy with the recommended starting dose.
Poor Metabolizer Very limited data available for CYP2D6 poor metabolizers Insufficient evidence demonstrating clinical impact; initiate therapy with the recommended starting dose.
Indeterminate No CPIC guidance for this phenotype Initiate therapy with the recommended starting dose.
Not available No CPIC guidance for this phenotype Initiate therapy with the recommended starting dose.

Alternative Treatment Options

Examples from CPIC guidelines include using granisetron, which is not predominantly metabolized by CYP2D6. Other 5-HT3 receptor antagonists or antiemetic classes may also be considered based on clinical judgment.

Sources and References

Disclaimer: This document is for informational purposes only and is not a substitute for medical advice. Clinical decisions should be made by a qualified healthcare professional.

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