European Journal of Clinical Pharmacology

, Volume 74, Issue 11, pp 1461–1469 | Cite as

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

  • Hironari Tanaka
  • Takafumi NaitoEmail author
  • Hikaru Sato
  • Takanori Hiraide
  • Yasuhide Yamada
  • Junichi Kawakami
Pharmacokinetics and Disposition



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.


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.


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.


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.


Tramadol Metabolite CYP Pharmacokinetics Cancer Interleukin-6 



This work was supported by JSPS KAKENHI Grant Numbers 15K08070 and 18H00398.

Compliance with ethical standards

This study was performed in accordance with the Declaration of Helsinki and its amendments, and the protocol was approved by the Ethics Committee of Hamamatsu University School of Medicine (16-288). This study is registered in the University Hospital Medical Information Network (UMIN-CTR UMIN000024060). The patients received information about the scientific aim of the study, and each patient provided written informed consent.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Hospital PharmacyHamamatsu University School of MedicineHamamatsuJapan
  2. 2.Department of Clinical OncologyHamamatsu University School of MedicineHamamatsuJapan

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