Rifampicin has a Profound Effect on the Pharmacokinetics of Oral S-Ketamine and Less on Intravenous S-Ketamine

• Published in: Basic & clinical pharmacology & toxicology Vol. 111; no. 5; pp. 325 - 332
• Main Authors: Peltoniemi, Marko A., Saari, Teijo I., Hagelberg, Nora M., Laine, Kari, Kurkinen, Kaisa J., Neuvonen, Pertti J., Olkkola, Klaus T.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.11.2012; Blackwell
• Subjects: Administration, Oral; Analgesics - administration & dosage; Analgesics - blood; Analgesics - pharmacokinetics; Biological and medical sciences; Biological Availability; Biotransformation - drug effects; Cross-Over Studies; Drug Interactions; Enzyme Induction - drug effects; Enzyme Inhibitors - pharmacology; Female; Half-Life; Humans; Indexing in process; Injections, Intravenous; Ketamine - administration & dosage; Ketamine - analogs & derivatives; Ketamine - blood; Ketamine - pharmacokinetics; Male; Medical sciences; Metabolic Clearance Rate; Pharmacology. Drug treatments; Psychomotor Performance - drug effects; Rifampin - pharmacology; Sleep Stages - drug effects; Intravenous administration; Oral administration; Glutamate receptor; Antibiotic; Ketamine; Rifampicin; General anesthetic; Antituberculous agent; Antagonist; Protein synthesis inhibitor; NMDA receptor; Antibacterial agent; Pharmacokinetics
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/j.1742-7843.2012.00908.x

Low‐dose ketamine is currently used in several acute and chronic pain conditions as an analgesic. Ketamine undergoes extensive metabolism and is thus susceptible to drug–drug interactions. We examined the effect rifampicin, a well‐known inducer of many cytochrome P450 (CYP) enzymes and transporters, on the pharmacokinetics of intravenous and oral S‐ketamine in healthy volunteers. Eleven healthy volunteers were administered in randomized order 600 mg rifampicin or placebo orally for 6 days in a four‐session paired cross‐over study. On day 6, S‐ketamine was administered intravenously (0.1 mg/kg) in the first part of the study and orally (0.3 mg/kg) in the second part. Plasma concentrations of ketamine and norketamine were measured up to 24 hr and behavioural and analgesic effects up to 12 hr. Rifampicin treatment decreased the mean area under the plasma ketamine concentration–time curve extrapolated to infinity (AUC 0–∞) of intravenous and oral S‐ketamine by 14% (p = 0.005) and 86% (p < 0.001), respectively. Rifampicin decreased greatly the peak plasma concentration of oral S‐ketamine by 81% (p < 0.001), but shortened only moderately the elimination half‐life of intravenous and oral S‐ketamine. Rifampicin decreased the ratio of norketamine AUC 0–∞ to ketamine AUC 0–∞ after intravenous S‐ketamine by 66%, (p < 0.001) but increased the ratio by 147% (p < 0.001) after the oral administration of S‐ketamine. Rifampicin profoundly reduces the plasma concentrations of ketamine and norketamine after oral administration of S‐ketamine, by inducing mainly its first‐pass metabolism.