Abstracts and Programme: EUROANAESTHESIA 2011: The European Anaesthesiology Congress: ESA Best Abstract Prize Competition (BAPC)
Background: An influence of polymorphic CYP2D6 genetic variants on antiemetic efficacy of ondansetron has been suggested [1,2]. However, the role of CYP3A in ondansetron metabolism has been obscure up to date. In this study the hypothesis that genotype dependent CYP2D6 and CYP3A activity selectively influences plasma concentrations of ondansetron enantiomers was evaluated. Additionally, the effects of doubling the ondansetron dose on genotype dependent plasma concentrations was investigated exploratively.
Methods: After approval of the local ethics committee and written informed consent patients scheduled for major abdominal surgery received i.v. ondansetron 4 mg (group O-4) or 8 mg (group O-8) for prophylaxis of PONV. CYP2D6 dependent activity score representing no, decreased, normal or increased CYP2D6 enzyme activity and CYP3A low (CYP3A5*3/*3) or high expressor status (CYP3A5*1/*1 or *1/*3) were determined by real-time PCR. Plasma concentrations of R- and S-ondansetron were measured by liquid chromatography-tandem mass spectrometry. Areas under the time concentration curves (AUC) of R- and S-ondansetron concentrations were associated to CYP2D6 and CYP3A5 genotype dependent enzyme activity.
Results: Complete data of 141 subjects could be analyzed. Concentrations of S-ondansetron differed between CYP2D6 activity groups (p=0.04) with highest measures in patients with no CYP2D6 activity (mean (5/95% CI): 362.5 (238.3/486.7) h·ng/ml) and lowest concentrations in those with increased activity (149.6 (114.5/184.8) h·ng/ml) compared to subject displaying genotypes resulting in reduced or normal CYP2D6 activity (263.6 (228.8/298.8), 255.4 (228.2/282.7) h·ng/ml). AUC of R-ondansetron was two-times higher in CYP3A5 low expressors compared to high expressors: (281.5 (248.6/314.3) vs. 142.5 (92.4/192.7) h·ng/ml; p=0.009. Doubling the ondansetron dose only increased plasma concentrations in individuals with low CYP3A5 activity with no increase in individuals with high enzyme activities (p< 0.001).
Conclusions: Metabolism of ondansetron seems to be enantioselective. Genetically and environmentally determined CYP2D6 and CYP3A enzyme activity might have implications for antiemetic efficacy.
1. Candiotti KA et al. Anesthesiology 2005;102:543
2. Janicki PK et al. Anesth Analg 2006;102:1127
Acknowledgements: The study was supported in part by the R. Sackler Research Foundation.