Pharmacokinetics, bioavailability and tissue distribution study of JCC-02, a novel N-methyl-d-aspartate (NMDA) receptor inhibitor, in rats by LC-MS/MS

Abstract JCC-02, N -(3,5-dimethyladamantan-1-yl)- N ′-(3-chlorophenyl) urea, has been developed as a novel N -methyl- d -aspartate (NMDA) receptor inhibitor for the treatment of Alzheimer's disease (AD). In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to determine the concentration of JCC-02 in rat plasma and different tissues to investigate its pharmacokinetic behavior in vivo and distribution character in organs. The matrix samples were prepared by protein precipitation method with acetonitrile using gliclazide as the internal standard (IS). This validated method was successfully applied to JCC-02 pharmacokinetic study in rats after oral administration of low (0.7 mg·kg −1 ), medium (2 mg·kg −1 ) and high (6 mg·kg −1 ) concentration, intravenous administration (2 mg·kg −1 ) as well as tissue distribution in rats after administration of JCC-02 (2 mg·kg −1 ) orally. The results indicated that the area under the time curve (AUC 0-∞ ) and peak plasma concentration (C max ) were directly proportional to dosage and the pharmacokinetic behavior of JCC-02 in rats was a linear process with respect to dosage. JCC-02 could be absorbed into blood circulation rapidly because of its short time to reach peak plasma concentration (t max ). Meanwhile, JCC-02 has a low clearance and a high volume of distribution, which might result in its long half-time. Oral absolute bioavailability (F) of JCC-02 was (14.61 ± 5.81)%, which was turned out to be low relatively. In tissues, the differences of JCC-02 concentration were quite large. After administration, small intestine (22.29 ± 15.86 μg·mL −1 ), stomach (7.21 ± 2.87 μg·mL −1 ), large intestine (1.27 ± 0.57 μg·mL −1 ), liver (0.96 ± 0.52 μg·mL −1 ) and fat (0.48 ± 0.24 μg·mL −1 ) were the first five organs with the largest drug concentration. Small intestine could be the main part of drug absorption where most of the drug was distributed after oral administration. More importantly, JCC-02 could cross the blood-brain barrier (BBB), which may probably have a pretty good therapeutic effect on AD.