Impact of Functional Allelic Variations on Drug-Drug Interactions Involving CYP2D6

Abstract

CYP2D6 genetically-predicted Extensive Metabolizers (gEMs) may carry one or two functional alleles. Currently phenotypes of carriers of two fully-functional alleles (genetic activity score 2, gAS2) and carriers of one fully-functional and one non-functional allele (genetic activity score 1, gAS1) are predicted EMs. However, drug-drug interactions (DDIs) might be underestimated among gAS1 patients. This study explores the impact of functional allelic variations on DDIs among gEMs. 34 healthy volunteers were allocated to two parallel study groups: gAS1 and gAS2. Dextromethorphan/dextrorphan metabolic ratio (UMR) in urine sampled for 10 hours after administration of 5 mg dextromethorphan was used to determined CYP2D6 phenotype in each of three study sessions. Volunteers additionally received 12 and 2 hours prior to dextromethorphan administration 60 mg of duloxetine in session 2 and 20 mg of paroxetine in session 3. Baseline phenotype distribution was not significantly different between the two genotypes. Higher proportion of IM was observed with the moderate inhibitor duloxetine: 71% of gAS1 and 25% of gAS2 subjects (p=0.009). With the strong inhibitor paroxetine, almost all gAS1 subjects were phenoconverted into PM (94%) whereas this proportion was lower in gAS2 subjects (56%, p=0.011). UMR values were significantly higher in gAS1 subjects than in gAS2 subjects in all conditions tested: 0.030 (CI95% 0.027–0.070) versus 0.009 (CI95% 0.007–0.022) (p=0.006) at baseline, 0.046 (CI95% 0.039–0.093) versus 0.017 (CI95% 0.012–0.038) with duloxetine (p=0.005) and 1.106 (CI95% 1.052–1.650) versus 0.344 (CI95% 0.249–0.745) with paroxetine (p<0.001). The proportion of PM phenoconversion with a strong inhibitor is higher in gEMs subjects carrying a non-functional CYP2D6 allele. Therefore, those individuals might be prone to adverse drug-drug interactions and might benefit from special attention when administered a CYP2D6 inhibitor.