Brain penetration of ketamine: Intranasal delivery VS parenteral routes of administraion

Ketamine is approved by the FDA to be used as an anesthetic however, recent reports have exhibited its success in the treatment of major depressive disorder (MDD). Studies have suggested that a sub-anesthetic dose produces rapid antidepressant activity providing significant symptomatic relief particularly in patients with a history of treatment resistant depression (TRD). Many reports have been published on the intranasal (IN) efficacy of ketamine in the treatment of depression, however studies that have investigated the effects of the route of administration on drug delivery to the brain appear to be absent in literature. Therefore, in this study, a single dose (15 mg/kg body weight) was administered via different routes of administration [oral (PO), intranasal (IN) and intraperitoneal (IP)] to healthy male Sprague-Dawley rats in order to determine the brain tissue pharmacokinetics of ketamine. A novel validated liquid chromatography-mass spectrometry (LC-MS) method was developed using a fused core column for the determination of ketamine in plasma and brain homogenates. While IP administration resulted in favorable concentrations in the brain and plasma; IN administration, which is supposed to favour drug delivery to the brain, exhibited moderately low drug levels post administration. PO administration produced significantly lower levels due to extensive first-pass metabolism in the liver and intestines. These results have implications for future studies exploring the use of ketamine for the treatment of MDD in order to optimize treatment regimens and suggest that parenteral administration of ketamine should be used in the treatment of depression.