Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers

Abstract

Ketamine is known to provide analgesic effects without an anesthetic when administered in a low dose. We previously reported that a tablet containing ketamine had analgesic effects in patients with neuropathic pain. In the present study, we compared the plasma concentration profiles of the enantiomers of ketamine and its active metabolite, norketamine, up to 8 h after the administration of 20 mg of ketamine by injection, after the administration of two tablets containing 25 mg of ketamine, after the administration of two sublingual tablets containing 25 mg of ketamine, after the insertion of a suppository containing 50 mg of ketamine, and after the application of a nasal spray containing 25 mg of ketamine to three healthy volunteers. The plasma concentration of ketamine biexponentially declined after the administration by injection; the value of T(1/2beta) for ketamine was approximately 120 min. The bioavailability of the tablet was estimated to be approximately 20%; the area under the plasma concentration-time curve, (AUC)(0-->8 h), of norketamine was approximately 500 ng h/ml in both enantiomers. The bioavailabilities of the sublingual tablet and the suppository were estimated to both be approximately 30%; the AUC(0-->8 h) of norketamine was 280-460 ng h/ml in both enantiomers. The plasma concentration profiles of the sublingual tablet and the suppository were almost similar to that of the tablet. The bioavailability of the nasal spray was estimated to be approximately 45%, which was the highest value among the preparations tested, and the AUC(0-->6 h) of norketamine was low (approximately 100 ng h/ml) in both enantiomers. These pharmacokinetic findings suggested that all of the ketamine preparations tested in this study may be useful for the alleviation of neuropathic pain. We propose that the type of ketamine preparation should be selected in accordance with the patient's disease condition and the required dosage amount of ketamine.

CE provides evidence of the stereoselective hydroxylation of norketamine in equines

“…1). It is typically administered as racemate although S-ketamine is more potent than R-ketamine and exhibits a greater clearance and faster anesthetic recovery compared with the racemate [1][2][3][4][5][6][7][8].…”

Use of Human Microsomes and Deuterated Substrates: An Alternative Approach for the Identification of Novel Metabolites of Ketamine by Mass Spectrometry

“…It is also used recreationally as a "club drug" (Degenhardt et al, 2005;Kenyon et al, 2005;Leong et al, 2005), and there is a concern that ketamine may be used to facilitate sexual assault. Methods developed to analyze ketamine and norketamine in various biological matrices are widespread (Bolze and Boulieu, 1998;Yanagihara et al, 2003;Lua and Lin, 2004;Adamowicz and Kala, 2005;Leong et al, 2005;Negrusz et al, 2005;Wang et al, 2005;Apollonio et al, 2006;Xiang et al, 2006) but the analysis of the secondary metabolite dehydronorketamine, and hydroxylated metabolite (both intact and conjugated), is much less common (Adams et al, 1981;Bolze and Boulieu, 1998;Hijazi et al, 2001). At the time of this work, the lack of commercial standards has hindered analysis of these metabolites, whose identification requires custom synthesis (Huang et al, 2005;Wu et al, 2007).…”

Intravenous Therapies in the Management of Neuropathic Pain: A Review on the Use of Ketamine and Lidocaine in Chronic Pain Management

“…Particularly, oral administration of ketamine is accompanied by extensive first-pass metabolism, and the plasma levels of (R and S)-norketamine are about three times higher than the levels produced by IV or IM administration (Yanagihara 2003). Nor Ketamine, which is excreted in urine, is thought to have about 30% of the analgesic potency of the parent drug (Sinner & Graf, 2008).…”