Significantly lower CYP2D6 metabolism measured as the O/N‐desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients

Abstract

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.

Quantification of In Vivo Metabolic Activity of CYP2D6 Genotypes and Alleles Through Population Pharmacokinetic Analysis of Vortioxetine

“…This is supported by recent findings from Haslemo et al 22 who found that carriers of CYP2D6*41 had a significantly lower CYP2D6-mediated metabolism of venlafaxine compared with a pooled group of CYP2D6*9−10 carriers. Based on the metabolic ratio of O/N-desmethylvenlafaxine, they estimated an activity score of 0.095 for CYP2D6*41 and 0.34 for CYP2D6*9-10.…”

Impairment of endoxifen formation in tamoxifen‐treated premenopausal breast cancer patients carrying reduced‐function CYP2D6 alleles

“…Interestingly, a recent study based on >1000 Norwegian samples from routine therapeutic drug monitoring of the antidepressant venlafaxine arrived at a similar conclusion regarding a surprisingly great impact of the CYP2D6*41 allele on the individual metabolic capacity. 14 It follows that the group of poor bioactivators of tamoxifen in clinical practice might be substantially larger than now understood from the definition of PM, which is currently restricted to carriers of 2 null alleles. In several studies, such PM patients have been associated with a worse prognosis than other genotypes during adjuvant treatment with tamoxifen 6-9,29 but perhaps the conservative PM definition will fail to detect that additional CYP2D6 genotypes with very low metabolic activity also could be at high risk of treatment failure.…”

“…The overall idea would be to use this patient stratification for individualized dose recommendations based on CYP2D6 genotype. However, intermediate metabolizers include a wide range of different allele combinations that clearly differ in their corresponding impact on the individual CYP2D6 metabolic activity, 13–17 and, for some variant alleles, this might even be explained by substrate‐dependent alterations in metabolic activity 18 . It follows that the conventional approach to ascribe all reduced‐function CYP2D6 alleles an anticipated 50% reduction of metabolic capacity compared to normal/fully functional alleles, is indeed simplistic and should be open for corrections over time 13 .…”

Optimising Seniors’ Metabolism of Medications and Avoiding Adverse Drug Events Using Data on How Metabolism by Their P450 Enzymes Varies with Ancestry and Drug–Drug and Drug–Drug–Gene Interactions

“…The ratio of the metabolism of venlafaxine in the primary metabolic pathway to O-desmethylvenlafaxine to N-desmethylvenlafaxine in the secondary metabolic pathway in the CYP2D6 isoform was used to identify variant alleles. The metabolic ratio varied from 0.47 for the Null/Null genotype to 68.18 for the *1/*4XN or *1/*41Xn ultrarapid metabolisers, demonstrating the importance of identifying the patients' genomics to be aware of the wide ranges of metabolism [80].…”