Key result
Carriers of the CYP2D6*41 allele had a significantly lower O/N-desmethylvenlafaxine metabolic ratio than CYP2D6*9-10 carriers (P<0.002), corresponding to calculated activity scores of 0.095 vs 0.34.
Why the study?
Does CYP2D6*41 allele carrier status reduce O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio compared to CYP2D6*9-10 in patients taking venlafaxine?
Observational (n=1,003)
No
Does CYP2D6*41 allele carrier status reduce O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio compared to CYP2D6*9-10 in patients taking venlafaxine?
CYP2D6*41 has a significantly lower enzyme activity score than CYP2D6*9 and *10, suggesting these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.
Answers are grounded in this paper and cite their sources.
CYP2D6*41 may warrant distinct activity scoring from *9/*10; observational data leave open impact on venlafaxine dosing.
AIMS: CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. METHODS: A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. RESULTS: MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P < 0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9-10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. CONCLUSIONS: CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.
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Haslemo et al. (2018) conducted an observational in CYP2D6 metabolism in venlafaxine treatment (n=1,003). CYP2D6*41 allele vs. CYP2D6*9 or CYP2D6*10 alleles was evaluated on O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) (p=< 0.002). Carriers of the CYP2D6*41 allele had a significantly lower O/N-desmethylvenlafaxine metabolic ratio than CYP2D6*9-10 carriers (P<0.002), corresponding to calculated activity scores of 0.095 vs 0.34.
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