Alteration in the plasma concentration of a DAAO inhibitor, 3-methylpyrazole-5-carboxylic acid, in the ketamine-treated rats and the influence on the pharmacokinetics of plasma D-tryptophan

Abstract

A determination method for 3-methylpyrazole-5-carboxylic acid (MPC), an inhibitor of d-amino acid oxidase (DAAO), in rat plasma was developed by using high-performance liquid chromatography-mass spectrometry (LC-MS). The structural isomer of MPC, 3-methylpyrazole-4-carboxylic acid, was used as an internal standard, and the intra- and inter-day accuracies and precisions were satisfactory for the determination of plasma MPC.Next, the LC-MS method was applied to determine the plasma MPC concentration in ketamine (Ket)-treated rats after intraperitoneal administration of MPC (5.0 or 50 mg·kg−1). The Cmax value of plasma MPC concentration in the Ket-treated rats was significantly higher than that in the control group when a high dose of MPC (50 mg·kg−1) was administered. In addition, it was found that plasma d-tryptophan (d-Trp) concentration in Ket-treated rats administered d-Trp was not significantly increased by MPC, suggesting that the DAAO-inhibitory effect of MPC is attenuated in Ket-treated rats.