Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting.

Postoperative nausea and vomiting (PONV) affects approximately one third of patients and may lead to aspiration, dehiscence, esophageal rupture, and increased treatment costs if inadequately controlled. An important therapeutic option for prevention of PONV is 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists. Nonetheless, therapeutic failure sometimes occurs. Metabolism by the cytochrome P450 (CYP) system differs among the 5-HT3 receptor antagonists, and provides a rational explanation for decreased therapeutic efficacy in some patients. Four of the 5-HT3 receptor antagonist agents (dolasetron, ondansetron, palonosetron, and tropisetron) are metabolized in various degrees via CYP2D6, 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, resulting in decreased efficacy for preventing PONV. Granisetron is the only agent in this class that is not metabolized via CYP2D6. Instead, granisetron is metabolized via the CYP3A4 isoform, which is not subject to significant genetic polymorphism. CYP2D6 genotype screening prior to PONV treatment may allow for modification of antiemetic dosing. An alternative is to use a 5-HT3 agent that is metabolized independently of the CYP2D6 isoform, such as granisetron, that would obviate the need for genotyping and may lead to improved prophylaxis of PONV.