title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku, Kiinamyllynkatu 4-8, P.O. Box 52, FI-20520 Turku, Finland.
authors.forename: Nora M
authors.initials: NM
authors.lastname: Hagelberg
authors.forename: Tuukka
authors.initials: T
authors.lastname: Saarikoski
authors.forename: Teijo I
authors.initials: TI
authors.lastname: Saari
authors.forename: Mikko
authors.initials: M
authors.lastname: Neuvonen
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Miia
authors.initials: M
authors.lastname: Turpeinen
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001711:Biotransformation; D018592:Cross-Over Studies; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors; D013988:Ticlopidine / Q000008:administration & dosage / Q000494:pharmacology*; D014147:Tramadol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D065692:Cytochrome P-450 CYP3A Inhibitors; C080580:O-demethyltramadol; D017964:Itraconazole; D014147:Tramadol; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; D013988:Ticlopidine