Exposure to Oral S-ketamine Is Unaffected by Itraconazole but Greatly Increased by Ticlopidine




Peltoniemi MA, Saari TI, Hagelberg NM, Reponen P, Turpeinen M, Laine K, Neuvonen PJ, Olkkola KT

PublisherNATURE PUBLISHING GROUP

2011

Clinical Pharmacology and Therapeutics

CLINICAL PHARMACOLOGY & THERAPEUTICS

CLIN PHARMACOL THER

2

90

2

296

302

7

0009-9236

DOIhttps://doi.org/10.1038/clpt.2011.140



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-infinity)) 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-infinity) to ketamine AUC(0-infinity) 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.



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