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. 2022 Oct 12;14(10):2177.
doi: 10.3390/pharmaceutics14102177.

An Investigation of O-Demethyl Tramadol/Tramadol Ratio for Cytochrome P450 2D6 Phenotyping: The CYTRAM Study

Blandine De La Gastine  1 , Soizic Percevault  1 , Laurent Varin  2 , Nicolas Richard  3   4 , Fabienne Fobe  5 , Benoît Plaud  6 , Georges Daccache  5 , Vincent Compere  7 , Jean-Jacques Parienti  8 , Antoine Coquerel  9 , Magalie Loilier  10 , Nathalie Bleyzac  1 , Laurent Bourguignon  1   11   12 , Sylvain Goutelle  1   11   12 , Véronique Lelong-Boulouard  9   10
Affiliations

An Investigation of O-Demethyl Tramadol/Tramadol Ratio for Cytochrome P450 2D6 Phenotyping: The CYTRAM Study

Blandine De La Gastine et al. Pharmaceutics. .

Abstract

Cytochrome P450 2D6 (CYP2D6) gene polymorphisms influence the exposure to tramadol (T) and its pharmacologically active metabolite, O-demethyl tramadol (O-dT). Tramadol has been considered as a candidate probe drug for CYP2D6 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for CYP2D6 phenotyping. European adult patients who received IV tramadol after surgery were included. CYP2D6 genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) CYP2D6 metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and CYP2D6 phenotype was examined in both a learning and a validation group. Genotype data were obtained in 301 patients, including 23 PM (8%), 117 IM (39%), 154 EM (51%), and 7 UM (2%). Tramadol trough concentrations at 24 h were available in 297 patients. Mean value of O-dT/T ratio was significantly lower in PM than in non-PM individuals (0.061 ± 0.031 versus 0.178 ± 0.09, p < 0.01). However, large overlap was observed in the distributions of O-dT/T ratio between groups. Statistical models based on O-dT/T ratio failed to identify CYP2D6 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for CYP2D6 phenotyping.

Keywords: CYP2D6; pharmacogenetics; pharmacogenomics; tramadol.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flowchart of data analysis.
Figure 2
Figure 2
Distribution of O-dT/T ratio at 24 h in PM and non-PM. Upper panel, histogram of phenotype counts; lower panel, violin plot of metabolic (O-dT/T) ratios. The colored dots represent individual data, the large red filled circle represents the mean value, the black solid line shows the probability density of data.
Figure 3
Figure 3
Distribution of O-dT/T ratio at 24 h in all phenotype groups. Upper panel, histogram of phenotype counts; lower panel, violin plot of metabolic (O-dT/T) ratios. The colored dots represent individual data, the large red filled circle represents the mean value, the black solid line shows the probability density of data.
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