title: Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine.
abstract: This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) of oral ketamine by 2.4-fold (P < 0.001), whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0-∞) to ketamine AUC(0-∞) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine.
authors.affiliation: Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: M A
authors.initials: MA
authors.lastname: Peltoniemi
authors.forename: T I
authors.initials: TI
authors.lastname: Saari
authors.forename: N M
authors.initials: NM
authors.lastname: Hagelberg
authors.forename: P
authors.initials: P
authors.lastname: Reponen
authors.forename: M
authors.initials: M
authors.lastname: Turpeinen
authors.forename: K
authors.initials: K
authors.lastname: Laine
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: K T
authors.initials: KT
authors.lastname: Olkkola
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000778:Anesthetics, Dissociative / Q000493:pharmacokinetics / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018592:Cross-Over Studies; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D007649:Ketamine / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013988:Ticlopidine / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000778:Anesthetics, Dissociative; D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D010975:Platelet Aggregation Inhibitors; D017964:Itraconazole; D007649:Ketamine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D013988:Ticlopidine; C033419:norketamine