Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonistsfor postoperative nausea and vomiting.
Piotr K Janicki
Med Sci Monit 2005; 11(10): RA322-328
Postoperative nausea and vomiting (PONV) affects approximately one thirdof patients and may lead to aspiration, dehiscence, esophageal rupture, and increased treatment costsif inadequately controlled. An important therapeutic option for prevention of PONV is 5-hydroxytryptaminetype 3 (5-HT3) receptor antagonists. Nonetheless, therapeutic failure sometimes occurs. Metabolism bythe cytochrome P450 (CYP) system differs among the 5-HT3 receptor antagonists, and provides a rationalexplanation for decreased therapeutic efficacy in some patients. Four of the 5-HT3 receptor antagonistagents (dolasetron, ondansetron, palonosetron, and tropisetron) are metabolized in various degrees viaCYP2D6, an isoform subject to marked genetic polymorphism. In patients with duplicate CYP2D6 alleles,degradation into inactive metabolites occurs rapidly with these four 5-HT3 receptor antagonists, resultingin decreased efficacy for preventing PONV. Granisetron is the only agent in this class that is not metabolizedvia CYP2D6. Instead, granisetron is metabolized via the CYP3A4 isoform, which is not subject to significantgenetic polymorphism. CYP2D6 genotype screening prior to PONV treatment may allow for modification ofantiemetic dosing. An alternative is to use a 5-HT3 agent that is metabolized independently of the CYP2D6isoform, such as granisetron, that would obviate the need for genotyping and may lead to improved prophylaxisof PONV.
Keywords: Genotype, Cytochrome P-450 Enzyme System - metabolism, Cytochrome P-450 CYP2D6 - metabolism, Humans, Postoperative Nausea and Vomiting - prevention & control, Serotonin 5-HT3 Receptor Antagonists, Serotonin Antagonists - therapeutic use