Investigation of O-demethyl tramadol/tramadol ratio for cytochrome P450 2D6 phenotyping: The CYTRAM study

Cytochrome P450 2D6 () 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 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for phenotyping. European adult patients who received IV tramadol after surgery were included. genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and 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, < 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 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for phenotyping.