Clarithromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S‐ketamine
Nora M. Hagelberg, Marko A. Peltoniemi, Teijo I. Saari, Kaisa J. Kurkinen, Kari Laine, Pertti J. Neuvonen, Klaus Tapio Olkkola
European Journal of Pain November 8, 2009 DOI: 10.1016/j.ejpain.2009.10.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled cross-over study Peer reviewed |
|---|---|
| Sample size | 10 |
| Population | Healthy subjects |
| Interventions | Clarithromycin S-ketamine |
| Dose | 0.2mg/kg of S-ketamine syrup |
| Duration | 4 days of pre-treatment; plasma concentrations measured for 24h; psychomotor effects followed for 12h |
| Topics | Esketamine Ketamine |
| Citations | 55 |
| Key points | Clarithromycin increased mean peak plasma ketamine concentration 3.6-fold and total exposure 2.6-fold, and decreased the CYP3A-dependent metabolite norketamine by 54%. Self-rated drug effect was enhanced, but cold pain scores and other behavioral effects were not affected. The authors attribute the increase to inhibition of CYP3A-mediated N-demethylation. |
Abstract
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.
Aim: AND
Methods: 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.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |
Citations in the library
Cited by 7
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Ketamine for chronic pain: risks and benefits British Journal of Clinical Pharmacology February 21, 2013
- The clinical toxicology of ketamine Clinical Toxicology June 2, 2023
- Metabolism and metabolomics of ketamine: a toxicological approach Forensic Sciences Research January 2, 2017
- The role of cytochrome P450 polymorphisms in the pharmacokinetics of oral esketamine. The pharmacogenomics journal April 24, 2026
and 2 more in the library