Impact of CYP genotype and inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patients.

Purpose: Clinical responses to oral tramadol show a large variation in cancer patients. This study aimed to evaluate the impacts of cytochrome P450 (CYP) genotype and serum inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patients.

Methods: The predose plasma concentrations of tramadol and its demethylated metabolites were determined at day 4 or later in 70 Japanese cancer patients treated with oral tramadol. The CYP genotypes, serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels, and the duration of tramadol treatment were evaluated.

Results: The CYP2D6 genotype did not affect the plasma tramadol concentration. The plasma concentration of O-desmethyltramadol and its ratio to tramadol were lower in the CYP2D6 intermediate and poor metabolizer (IM + PM) group than in the normal metabolizer (NM) group (P = 0.002 and P = 0.023). The plasma concentration of N-desmethyltramadol and its ratio to tramadol were higher in the CYP2D6 IM + PM group than in the NM group (P = 0.001 and P = 0.001). The CYP2B6*6 and CYP3A5*3 alleles had no effect on the plasma concentrations of tramadol and its demethylated metabolites. The serum IL-6 and CRP levels were inversely correlated with the plasma concentration ratios of N-desmethyltramadol to tramadol and of N,O-didesmethyltramadol to O-desmethyltramadol. The serum IL-6 level was associated with the treatment duration of oral tramadol.

Conclusions: The CYP2D6 genotype but not the CYP2B6 and CYP3A5 genotypes affected the plasma concentrations of O- and N-desmethyltramadol through alteration of the tramadol metabolic pathway. The serum IL-6 level was associated with N-demethylation activity and tramadol tolerability.