Pharmacokinetic and tissue distribution study of ZCY-15, a novel compound against Alzheimer's disease, in rats by liquid chromatography-tandem mass spectrometry.

Abstract ZCY-15, N-(3,5-dimethyladamatan-1-yl)-N-(3-methylphenyl) urea, is a candidate compound synthesized from the memantine structure and has been shown to be remarkably effective in treating Alzheimer's disease. To elucidate the pharmacokinetics and tissue distribution of ZCY-15 in rats after oral and intravenous administration, a rapid and selective LC-MS/MS method was established for the determination of ZCY-15 in rat plasma and tissues. According to the dissolution characteristics, the plasma samples were prepared by acetonitrile protein precipitation and carbamazepine was selected as the internal standard (IS). After separation by gradient elution using Aqela Venusil ASB C8 (2.1 × 50 mm, 3 µm), the pretreated samples were analyzed in MRM mode in positive ESI mode. The effective detection limit of this method was 1.95–1000 ng·mL−1. Tissue samples were collected from the heart, liver, spleen, lung, kidney, fat, muscle, brain, hippocampus, testicles or ovaries, large intestine, small intestine and stomach. The proposed method demonstrated fine precision and accuracy for analyzing ZCY-15 in selected tissues within the concentration range of standard liquid chromatography-tandem mass spectrometry. The whole analysis time was 3.6 min per sample. After oral administration, the blood and tissue concentrations of ZCY-15 in female rats were significantly higher than those in male rats. The clearance rate of ZCY-15 in female rats was lower than that in male rats. The results confirmed that there were gender differences. It has been shown that ZCY-15 could pass through the blood-brain barrier and was highly concentrated in the hippocampus. We established the first bioanalytical method to quantify ZCY-15 in rodent bio-samples for ongoing pharmacokinetic and tissue distribution studies, and the results were expected to lay foundation for the subsequent studies.