Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, Turku, Finland.
Basic Clin Pharmacol Toxicol. 2012 Nov;111(5):325-32. doi: 10.1111/j.1742-7843.2012.00908.x. Epub 2012 Jun 27.
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.
小剂量氯胺酮目前被用于几种急性和慢性疼痛病症的镇痛治疗。氯胺酮广泛代谢，因此易发生药物相互作用。我们研究了利福平（一种众所周知的许多细胞色素 P450（CYP）酶和转运蛋白的诱导剂）对健康志愿者静脉内和口服 S-氯胺酮药代动力学的影响。在一项四期配对交叉研究中，11 名健康志愿者随机接受 6 天 600 毫克利福平或安慰剂口服治疗。在第 6 天，在研究的第一部分静脉内给予 S-氯胺酮（0.1 毫克/千克），在第二部分口服给予 S-氯胺酮（0.3 毫克/千克）。在 24 小时内测量氯胺酮和去甲氯胺酮的血药浓度，在 12 小时内测量行为和镇痛效果。利福平治疗使静脉内和口服 S-氯胺酮的血浆氯胺酮浓度-时间曲线下面积（AUC（0-∞））分别降低 14%（p = 0.005）和 86%（p < 0.001）。利福平大大降低了口服 S-氯胺酮的血浆峰浓度，降低了 81%（p < 0.001），但仅适度缩短了静脉内和口服 S-氯胺酮的消除半衰期。利福平降低了静脉内给予 S-氯胺酮后去甲氯胺酮 AUC（0-∞）与氯胺酮 AUC（0-∞）的比值 66%（p < 0.001），但在口服给予 S-氯胺酮后增加了 147%（p < 0.001）。利福平主要通过诱导其首过代谢，显著降低口服 S-氯胺酮后氯胺酮和去甲氯胺酮的血浆浓度。
