Clarithromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine.
BACKGROUND
Oral ketamine is used as an adjuvant in the treatment of refractory neuropathic and cancer-related pain. Drug interactions may alter the analgesic or other effects of ketamine.


OBJECTIVE
The aim of the study was to investigate the effect of cytochrome P450 3A enzyme inhibition with clarithromycin on the pharmacokinetics and pharmacodynamics of oral S-ketamine in a randomized controlled cross-over study with two phases. Ten healthy subjects were pre-treated with oral clarithromycin or placebo for 4 days. On day 4, they ingested an oral dose of 0.2mg/kg of S-ketamine syrup. Plasma concentrations of ketamine and norketamine were measured for 24h. Analgesic effects were evaluated in a cold pressor test and psychomotor effects were followed for 12h.


RESULTS
Clarithromycin increased the mean C(max) of ketamine by 3.6-fold (p<0.001) and the mean AUC(0-infinity) of ketamine by 2.6-fold (p=0.001). The relative amount of the CYP3A dependent metabolite norketamine was decreased by 54% by clarithromycin (p=0.004). Self-rated drug effect of S-ketamine was enhanced by clarithromycin (p<0.05) but other behavioral effects or cold pain scores were not affected.


CONCLUSIONS
Clarithromycin strongly increases plasma concentrations of oral S-ketamine probably by inhibiting its CYP3A-mediated N-demethylation. This increase is reflected as modest changes in behavioral effects of oral S-ketamine.
Hagelberg
Nora M
NM
Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku, Turku, Finland. nora.hagelberg@tyks.fi
Peltoniemi
Marko A
MA
Saari
Teijo I
TI
Kurkinen
Kaisa J
KJ
Laine
Kari
K
Neuvonen
Pertti J
PJ
Olkkola
Klaus T
KT
D000328:Adult; D000700:Analgesics / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D017291:Clarithromycin / Q000008:administration & dosage* / Q000097:blood; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D010147:Pain Measurement / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000097:blood
D000700:Analgesics; D011500:Protein Synthesis Inhibitors; D007649:Ketamine; D017291:Clarithromycin