Pharmacokinetics and brain distribution of ketamine after nasal administration

J Pharm Biomed Anal. 2025 May 9;264:116945. doi: 10.1016/j.jpba.2025.116945. Online ahead of print.

ABSTRACT

Major depressive disorder is a severe mental condition characterized by abnormalities in the structure and function of the brain. Ketamine is a novel antidepressant that has rapid effects on depression. This drug is clinically used to treat depression in patients with acute suicidal ideation or behavior. It is typically administered at a dose of 84 mg. However, the distribution of ketamine in the body after intranasal administration, particularly in the brain, remains unknown. In the present study, we utilized a high-performance liquid chromatography-tandem mass spectrometry method to measure ketamine concentrations in rat plasma and several tissues. The measurement ranges were 5-8000 ng/mL for the plasma samples and 5-5000 ng/mL for the tissue samples. The pharmacokinetic profile revealed that the rat plasma ketamine concentration rapidly spiked to a peak of 8002 ng/mL within about 5 min, followed by a rapid decline, nearly reaching 0 ng/mL by about 3 h; the half-life was 27 min. Tissue distribution results revealed that ketamine concentrations in different tissues peaked at 5 min. The highest concentration was noted in the kidneys, followed by the liver. In the rat brain regions, ketamine was primarily concentrated in the hypothalamus and hippocampus, with lower concentrations in the striatum and prefrontal cortex. Our novel methodological approach and findings provide a significant theoretical foundation for using ketamine in clinical settings.

PMID:40375400 | DOI:10.1016/j.jpba.2025.116945