Pharmacokinetics, absolute bioavailability, and tissue distribution of WJ‐14, a novel N‐methyl‐d‐aspartate receptor antagonist, in rats by liquid chromatography–tandem mass spectrometry

Abstract

AbstractTo circumvent the limitations of current antidepressants, WJ‐14, a novel N‐methyl‐d‐aspartate receptor antagonist, was synthesized and demonstrated to have remarkable efficiency in the treatment of depression. To illustrate the pharmacokinetics, absolute bioavailability, and tissue distribution of WJ‐14 in rats, a rapid and sensitive liquid chromatography–tandem mass spectrometry–based analytical method was developed and validated for the separation and detection of WJ‐14 in both plasma and tissue samples. After oral administration, WJ‐14 was rapidly absorbed into the blood with time to reach the maximum plasma concentration (Tmax) within 0.28 h and quickly eliminated with clearance (Cl) exceeding 6.80 L/h/kg and elimination half‐life (t1/2) within 2.69 h. No obvious accumulation was found with mean residencetime (MRT) within 4.10 h. Tissue distribution revealed that WJ‐14 was extensively distributed in the main tissues of rats, and massive amounts of WJ‐14 were distributed in the liver. Extensive distribution and quick elimination led to extremely low absolute bioavailability of WJ‐14 (1.91% of 8.33 mg/kg and 3.30% of 24.99 mg/kg). WJ‐14 was detected in the brain only 0.083 h after oral administration, which is crucial for a rapid‐onset antidepressant candidate. In addition, WJ‐14 likely exhibited a non‐linear pharmacokinetic process at dosages of 8.33 and 24.99 mg/kg. The findings may provide valuable information for subsequent studies on WJ‐14.