Advertisement

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 Naito
  • Hikaru Sato
  • Takanori Hiraide
  • Yasuhide Yamada
  • Junichi Kawakami
Pharmacokinetics and Disposition
  • 189 Downloads

Abstract

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.

Keywords

Tramadol Metabolite CYP Pharmacokinetics Cancer Interleukin-6 

Notes

Funding

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

228_2018_2527_MOESM1_ESM.pptx (39 kb)
ESM 1 (PPTX 39 kb)
228_2018_2527_MOESM2_ESM.pptx (86 kb)
ESM 2 (PPTX 85.5 kb)
228_2018_2527_MOESM3_ESM.doc (50 kb)
ESM 3 (DOC 50 kb)
228_2018_2527_MOESM4_ESM.doc (47 kb)
ESM 4 (DOC 47 kb)

References

  1. 1.
    Grond S, Sablotzki A (2004) Clinical pharmacology of tramadol. Clin Pharmacokinet 43:879–892CrossRefGoogle Scholar
  2. 2.
    Barann M, Stamer UM, Lyutenska M, Stüber F, Bönisch H, Urban B (2015) Effects of opioids on human serotonin transporters. Naunyn Schmiedeberg's Arch Pharmacol 388:43–49CrossRefGoogle Scholar
  3. 3.
    Grond S, Radbruch L, Meuser T, Loick G, Sabatowski R, Lehmann KA (1999) High-dose tramadol in comparison to low-dose morphine for cancer pain relief. J Pain Symptom Manag 18:174–179CrossRefGoogle Scholar
  4. 4.
    Leppert W (2009) Tramadol as an analgesic for mild to moderate cancer pain. Pharmacol Rep 61:978–992CrossRefGoogle Scholar
  5. 5.
    Gillen C, Haurand M, Kobelt DJ, Wnendt S (2000) Affinity, potency and efficacy of tramadol and its metabolites at the cloned human μ-opioid receptor. Naunyn Schmiedeberg’s Arch Pharmacol 362:116–121CrossRefGoogle Scholar
  6. 6.
    Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG (2001) Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 29:1146–1155PubMedGoogle Scholar
  7. 7.
    Zanger UM, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 138:103–141CrossRefGoogle Scholar
  8. 8.
    Stamer UM, Lehnen K, Höthker F, Bayerer B, Wolf S, Hoeft A, Stuber F (2003) Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 105:231–238CrossRefGoogle Scholar
  9. 9.
    Dong H, Lu SJ, Zhang R, Liu DD, Zhang YZ, Song CY (2015) Effect of the CYP2D6 gene polymorphism on postoperative analgesia of tramadol in Han nationality nephrectomy patients. Eur J Clin Pharmacol 71:681–686CrossRefGoogle Scholar
  10. 10.
    Orliaguet G, Hamza J, Couloigner V, Denoyelle F, Loriot MA, Broly F, Garabedian EN (2015) A case of respiratory depression in a child with ultrarapid CYP2D6 metabolism after tramadol. Pediatrics 135:e753–e755CrossRefGoogle Scholar
  11. 11.
    Stamer UM, Stüber F, Muders T, Musshoff F (2008) Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg 107:926–929CrossRefGoogle Scholar
  12. 12.
    Ariyoshi N, Miyazaki M, Toide K, Sawamura Y, Kamataki T (2001) A single nucleotide polymorphism of CYP2b6 found in Japanese enhances catalytic activity by autoactivation. Biochem Biophys Res Commun 281:1256–1260CrossRefGoogle Scholar
  13. 13.
    Tsuchiya K, Gatanaga H, Tachikawa N, Teruya K, Kikuchi Y, Yoshino M, Kuwahara T, Shirasaka T, Kimura S, Oka S (2004) Homozygous CYP2B6*6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens. Biochem Biophys Res Commun 319:1322–1326CrossRefGoogle Scholar
  14. 14.
    Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383–391CrossRefGoogle Scholar
  15. 15.
    Poulsen L, Arendt-Nielsen L, Brøsen K, Sindrup SH (1996) The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 60:636–644CrossRefGoogle Scholar
  16. 16.
    Paar WD, Poche S, Gerloff J, Dengler HJ (1997) Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur J Clin Pharmacol 53:235–239CrossRefGoogle Scholar
  17. 17.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867CrossRefGoogle Scholar
  18. 18.
    Morley JE, Thomas DR, Wilson MM (2006) Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr 83:735–743CrossRefGoogle Scholar
  19. 19.
    Suzuki H, Asakawa A, Amitani H, Nakamura N, Inui A (2013) Cancer cachexia-pathophysiology and management. J Gastroenterol 48:574–594CrossRefGoogle Scholar
  20. 20.
    Aoyagi T, Terracina KP, Raza A, Matsubara H, Takabe K (2015) Cancer cachexia, mechanism and treatment. World J Gastrointest Oncol 7:17–29CrossRefGoogle Scholar
  21. 21.
    Slaviero KA, Clarke SJ, Rivory LP (2003) Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy. Lancet Oncol 4:224–232CrossRefGoogle Scholar
  22. 22.
    Morgan ET (2009) Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther 85:434–438CrossRefGoogle Scholar
  23. 23.
    Morgan ET, Goralski KB, Piquette-Miller M, Renton KW, Robertson GR, Chaluvadi MR, Charles KA, Clarke SJ, Kacevska M, Liddle C, Richardson TA, Sharma R, Sinal CJ (2008) Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer. Drug Metab Dispos 36:205–216CrossRefGoogle Scholar
  24. 24.
    Harvey RD, Morgan ET (2014) Cancer, inflammation, and therapy: effects on cytochrome p450-mediated drug metabolism and implications for novel immunotherapeutic agents. Clin Pharmacol Ther 96:449–457CrossRefGoogle Scholar
  25. 25.
    Lassen D, Damkier P, Brøsen K (2015) The pharmacogenetics of tramadol. Clin Pharmacokinet 54:825–836CrossRefGoogle Scholar
  26. 26.
    Petrone D, Kamin M, Olson W (1999) Slowing the titration rate of tramadol HCl reduces the incidence of discontinuation due to nausea and/or vomiting: a double-blind randomized trial. J Clin Pharm Ther 24:115–123CrossRefGoogle Scholar
  27. 27.
    Flockhart DA (2007) Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine. “/clinpharm/ddis/clinical-table/” accessed [10 July 2018]Google Scholar
  28. 28.
    Tanaka H, Naito T, Mino Y, Kawakami J (2016) Validated determination method of tramadol and its desmethylates in human plasma using an isocratic LC-MS/MS and its clinical application to patients with cancer pain or non-cancer pain. J Pharm Health Care Sci 2:25CrossRefGoogle Scholar
  29. 29.
    Fletcher B, Goldstein DB, Bradman AL, Weale ME, Bradman N, Thomas MG (2003) High-throughput analysis of informative CYP2D6 compound haplotypes. Genomics 81:166–174CrossRefGoogle Scholar
  30. 30.
    Sheng HH, Zeng AP, Zhu WX, Zhu RF, Li HM, Zhu ZD, Qin Y, Jin W, Liu Y, Du YL, Sun J, Xiao HS (2007) Allelic distributions of CYP2D6 gene copy number variation in the Eastern Han Chinese population. Acta Pharmacol Sin 28:279–286CrossRefGoogle Scholar
  31. 31.
    Wang G, Zhang H, He F, Fang X (2006) Effect of the CYP2D6*10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population. Eur J Clin Pharmacol 62:927–931CrossRefGoogle Scholar
  32. 32.
    Lang T, Klein K, Fischer J, Nüssler AK, Neuhaus P, Hofmann U, Eichelbaum M, Schwab M, Zanger UM (2001) Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 11:399–415CrossRefGoogle Scholar
  33. 33.
    Fukuen S, Fukuda T, Maune H, Ikenaga Y, Yamamoto I, Inaba T, Azuma J (2002) Novel detection assay by PCR-RFLP and frequency of the CYP3A5 SNPs, CYP3A5*3 and *6, in a Japanese population. Pharmacogenetics 12:331–334CrossRefGoogle Scholar
  34. 34.
    Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F (2007) Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther 82:41–47CrossRefGoogle Scholar
  35. 35.
    Saarikoski T, Saari TI, Hagelberg NM, Backman JT, Neuvonen PJ, Scheinin M, Olkkola KT, Laine K (2015) Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol. Eur J Clin Pharmacol 71:321–317CrossRefGoogle Scholar
  36. 36.
    Tzvetkov MV (2017) OCT1 pharmacogenetics in pain management: is a clinical application within reach? Pharmacogenomics 18:1515–1523CrossRefGoogle Scholar
  37. 37.
    Aitken AE, Morgan ET (2007) Gene-specific effects of inflammatory cytokines on cytochrome P450 2C, 2B6 and 3A4 mRNA levels in human hepatocytes. Drug Metab Dispos 35:1687–1693CrossRefGoogle Scholar
  38. 38.
    Jover R, Bort R, Gómez-Lechón MJ, Castell JV (2002) Down-regulation of human CYP3A4 by the inflammatory signal interleukin-6: molecular mechanism and transcription factors involved. FASEB J 16:1799–1801CrossRefGoogle Scholar
  39. 39.
    Dickmann LJ, Patel SK, Rock DA, Wienkers LC, Slatter JG (2011) Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in human hepatocyte culture. Drug Metab Dispos 39:1415–1422CrossRefGoogle Scholar
  40. 40.
    Cressman AM, Petrovic V, Piquette-Miller M (2012) Inflammation-mediated changes in drug transporter expression/activity: implications for therapeutic drug response. Expert Rev Clin Pharmacol 5:69–89CrossRefGoogle Scholar
  41. 41.
    Naito T, Takashina Y, Yamamoto K, Tashiro M, Ohnishi K, Kagawa Y, Kawakami J (2011) CYP3A5*3 affects plasma disposition of noroxycodone and dose escalation in cancer patients receiving oxycodone. J Clin Pharmacol 51:1529–1538CrossRefGoogle Scholar
  42. 42.
    Ishida T, Naito T, Sato H, Kawakami J (2016) Relationship between the plasma fentanyl and serum 4β-hydroxycholesterol based on CYP3A5 genotype and gender in patients with cancer pain. Drug Metab Pharmacokinet 31(3):242–248CrossRefGoogle Scholar
  43. 43.
    Nishida Y, Fukuda T, Yamamoto I, Azuma J (2000) CYP2D6 genotypes in a Japanese population: low frequencies of CYP2D6 gene duplication but high frequency of CYP2D6*10. Pharmacogenetics 10:567–570CrossRefGoogle Scholar
  44. 44.
    Meirovitz A, Kuten M, Billan S, Abdah-Bortnyak R, Sharon A, Peretz T, Sela M, Schaffer M, Barak V (2010) Cytokines levels, severity of acute mucositis and the need of PEG tube installation during chemo-radiation for head and neck cancer—a prospective pilot study. Radiat Oncol 5:16CrossRefGoogle Scholar

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

Personalised recommendations