Bioanalytical method for evaluating the pharmacokinetics of the GCP-II inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA)

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• 作者：Rana Rais ; Camilo Rojas ; Krystyna Wozniak ; Ying Wu ; Ming Zhao ; Takashi Tsukamoto ; Michelle A. Rudek ; Barbara S. Slusher
• 关键词：GCP-II ; glutamate carboxypeptidase-II ; PSMA ; prostate specific membrane antigen ; NAALADase ; N-acetylated-alpha-linked acidic dipeptidase ; NAAG ; N-acetyl-aspartyl glutamate ; 2-PMPA ; 2-phosphonomethyl pentanedioic acid ; 2-PMSA ; 2-phosphonomethyl succinic acid ; DRG ; dorsal root ganglion ; MTBSTFA ; N-tert-butyldimethysilyl-N-methyl trifluoroacetamide ; LLOQ ; lower limit of quantitation ; LQC ; low quality control ; MQC ; medium quality control ; HQC ; high quality control ; AULQ ; above upper limits of quanti
• 刊名：Journal of Pharmaceutical and Biomedical Analysis
• 出版年：25 January, 2014
• 年：2014
• 卷：88
• 期：Complete
• 页码：162-169
• 全文大小：549 K

文摘

2-Phosphonomethyl pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II, an enzyme which catabolizes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to N-acetylaspartate (NAA) and glutamate. 2-PMPA demonstrates robust efficacy in numerous animal models of neurological disease, however its pharmacokinetics has not yet been fully described. 2-PMPA is a highly polar compound with multiple negative charges causing significant challenges for analysis in biological matrices. Here we report a derivatization method for the acidic groups that involved protein precipitation with acetonitrile followed by reaction with N-tert-butyldimethysilyl-N-methyltrifluoroacetamide (MTBSTFA). The silylated analyte with transitions (683鈫?51.4) and the internal standard (669鈫?37.2) were monitored by tandem mass spectrometry with electrospray positive ionization mode. The method was subsequently used to evaluate 2-PMPA pharmacokinetics in rats. Intraperitoneal administration of 100 mg/kg 2-PMPA resulted in maximum concentration in plasma of 275 渭g/mL at 0.25 h. The half-life, area under the curve, apparent clearance, and volume of distribution were 0.64 h, 210 渭g 脳 h/mL, 7.93 mL/min/kg, and 0.44 L/kg, respectively. The tissue/plasma ratios in brain, sciatic nerve and dorsal root ganglion were 0.018, 0.120 and 0.142, respectively. In summary, a sensitive analytical method for 2-PMPA is reported that can be employed for similarly charged molecules.