Prevention of Post-operative Nausea and Vomiting with Granisetron and Dolasetron in relation to CYP 2D6 Genotype

An article published in the Journal of Anaesthesia and Analgesia studied the efficacy of granisetron and dolasetron in preventing post-operative nausea and vomiting with regards to the CYP 2D6 genotype. A prospective, randomised, double-blind study was conducted on the inter-relation of metabolic cytochrome P450 enzymes and 5HT3 antagonist anti-emetic drugs, such as granisetron and dolasetron. 150 adult patients were analysed based on their response to the anti-emetics administered and results were extrapolated for comparison of patient CYP 2D6 genotyping. Study observations lead to the postulation that differences in the CYP 2D6 genotype of patients translated to a difference in clinical efficacy of the two anti-emetics administered, particularly in dolasetron efficacy.

5-HT3 antagonists are commonly utilised in the prophylaxis and treatment of post-operative nausea and vomiting (PONV) due to their relative effectiveness over anti-nauseants. These anti-emetics share similar modes of action; however, differences do exist in their chemical structures, giving rise to variations in their pharmacokinetics. As such, the drugs within this class undergo metabolism through individualised pathways of the hepatic CYP 450 system. Of these, ondansetron, tropisetron, and dolasetron are metabolised by the genetically polymorphic CYP 2D6 isoform; while granisetron metabolism has been linked to the less polymorphic 3A4 isoform. Thus, this study undertook a direct comparison of the therapeutic efficacy of granisetron and dolasetron in the prevention of PONV. Furthermore, it extended its aims to conduct a preliminary appraisal of the effect of differing CYP 2D6 genotypes on therapeutic effectiveness of the two drugs. One hundred and fifty adult patients were randomly assigned into two groups, and were administered either granisetron 1 mg IV or dolasetron 12.5 mg IV. These anti-emetic doses were delivered 30 minutes before the cessation of surgery, and were then assessed for 24 hours post-operatively. Observations were made on vomiting, retching, or dry heaves experienced by patients, as well as patients’ requirement for anti-emetic ‘rescue’ therapy with promethazine.Genotyping analysis was also performed simultaneously for all participants using polymerase chain reaction (PCR) techniques. Four distinct polymorphic phenotypes arose for the 2D6 genotype, consisting of dysfunctional or deleted alleles; alleles with decreased function; 1 or 2 fully functioning alleles; or multiple normally functioning alleles. Patient examination revealed a statistically significant frequency of ‘rescue’ medication delivery in the dolasetron group, coupled with a more notable observation of nausea and vomiting episodes. Furthermore, there was a perceived increase in vomiting episodes for dolasetron patients displaying multiple normally functioning alleles. Such patients were designated ‘ultra metabolisers (UM)’ of the CYP 2D6 genotype. The results exhibited comparable efficacy of both drugs for PONV in the immediate period following surgery; however, notable differences arose in the efficacies during the consequent 24 hour patient assessment. A relative comparison of complete response to anti-emetics displays 54.7% of patients on granisetron as opposed to 38.7% on dolasetron, where ‘complete response’ was defined in terms of no observed PONV episodes. Moreover, there was an increased frequency of vomiting episodes noted in UM patients receiving dolasetron. This lead to implications of reduced efficacy with polymorphic variations of the CYP 2D6 genotype, which warrants further investigation comprising larger and more extensive trials on CYP genotype polymorphism vs. anti-emetic efficacy. Reference:Janicki PK, Schuler HG, Jarzembowski TM, et al. Prevention of post operative nausea and vomiting with granisetron and dolasetron. Anaesth Analg 2006; 102(4); 1127-33.