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Ticlopidine inhibits both O-demethylation and renal clearance of tramadol, increasing the exposure to it, but itraconazole has no marked effect on the ticlopidine-tramadol interaction

  • Pharmacokinetics and Disposition
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Abstract

Purpose

We assessed possible drug interactions of tramadol given concomitantly with the potent CYP2B6 inhibitor ticlopidine, alone or together with the potent CYP3A4 and P-glycoprotein inhibitor itraconazole.

Methods

In a randomized, placebo-controlled cross-over study, 12 healthy subjects ingested 50 mg of tramadol after 4 days of pretreatment with either placebo, ticlopidine (250 mg twice daily) or ticlopidine plus itraconazole (200 mg once daily). Plasma and urine concentrations of tramadol and its active metabolite O-desmethyltramadol (M1) were monitored over 48 h and 24 h, respectively.

Results

Ticlopidine increased the mean area under the plasma concentration-time curve (AUC0-∞) of tramadol by 2.0-fold (90 % confidence interval (CI) 1.6–2.4; p < 0.001) and Cmax by 1.4-fold (p < 0.001), and reduced its oral and renal clearance (p < 0.01). Ticlopidine reduced the AUC0-3 of M1 (p < 0.001) and the ratio of the AUC0-∞ of M1 to that of tramadol, but did not influence the AUC0-∞ of M1. Tramadol or M1 pharmacokinetics did not differ between the ticlopidine alone and ticlopidine plus itraconazole phases.

Conclusions

Ticlopidine increased exposure to tramadol, reduced its renal clearance and inhibited the formation of M1, most likely via inhibition of CYP2B6 and/or CYP2D6. The addition of itraconazole to ticlopidine did not modify the outcome of the drug interaction. Concomitant clinical use of ticlopidine and tramadol may enhance the risk of serotonergic effects, especially when higher doses of tramadol are used.

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Acknowledgments

We want to thank Mrs. Elina Kahra (medical laboratory technologist, Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Turku, Finland) for skillful technical assistance.

Funding

Turku University Hospital research fund EVO 13821, Turku, Finland

Author information

Authors and Affiliations

  1. Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku, Kiinamyllynkatu 4-8, P.O. Box 52, FI-20520, Turku, Finland

    Nora M. Hagelberg, Tuukka Saarikoski & Klaus T. Olkkola

  2. Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Teijo I. Saari

  3. Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland

    Mikko Neuvonen & Pertti J. Neuvonen

  4. Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland

    Miia Turpeinen

  5. Department of Pharmacology, Drug Development and Therapeutics, University of Turku, and TYKSLAB, Turku University Hospital, Turku, Finland

    Mika Scheinin & Kari Laine

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  1. Nora M. Hagelberg
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  2. Tuukka Saarikoski
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  3. Teijo I. Saari
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  9. Klaus T. Olkkola
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Correspondence to Tuukka Saarikoski.

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The contributions of Nora M. Hagelberg and Tuukka Saarikoski in the study were equal

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Hagelberg, N.M., Saarikoski, T., Saari, T.I. et al. Ticlopidine inhibits both O-demethylation and renal clearance of tramadol, increasing the exposure to it, but itraconazole has no marked effect on the ticlopidine-tramadol interaction. Eur J Clin Pharmacol 69, 867–875 (2013). https://doi.org/10.1007/s00228-012-1433-0

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  • DOI: https://doi.org/10.1007/s00228-012-1433-0

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