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, 13)

1 HCL - Hospices Civils de Lyon
2 Hôpital Privé d'Antony
3 Service de Génétique [CHU Caen]
4 BIOTARGEN - Biologie, génétique et thérapies ostéoarticulaires et respiratoires
5 Service d'Anesthésie - Réanimation Chirurgicale [CHU Caen]
6 Service d'anesthésie-réanimation-CTB [CHU Saint Louis]
7 IRIB - Institute for Research and Innovation in Biomedicine
8 Direction de la Recherche Clinique et de l'innovation
9 COMETE - Mobilités : Vieillissement, Pathologie, Santé
10 Département de Pharmacologie [CHU Caen]
11 LBBE - Laboratoire de Biométrie et Biologie Evolutive - UMR 5558
12 Université de Lyon
13 Service de Pharmacologie

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.

Mots clés: CYP2D6; pharmacogenetics; pharmacogenomics; tramadol

Domaines: Médecine vétérinaire et santé animale

Blandine de la Gastine, Soizic Percevault, Laurent Varin, Nicolas Richard, Fabienne Fobe, et al.. An Investigation of O-Demethyl Tramadol/Tramadol Ratio for Cytochrome P450 2D6 Phenotyping: The CYTRAM Study. Pharmaceutics, 2022, 14 (10), pp.2177. ⟨10.3390/pharmaceutics14102177⟩. ⟨hal-03842709⟩