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

Rana Rais, Camilo Rojas, Krystyna Wozniak, Ying Wu, Ming Zhao, Takashi Tsukamoto, Michelle A. Rudek, Barbara S. Slusher

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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→551.4) and the internal standard (669→537.2) 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. μg/mL at 0.25. h. The half-life, area under the curve, apparent clearance, and volume of distribution were 0.64. h, 210. μg. ×. 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.

Original languageEnglish (US)
Pages (from-to)162-169
Number of pages8
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume88
DOIs
StatePublished - Jan 25 2014

Keywords

  • 2-PMPA
  • Brain/plasma ratio
  • Derivatization
  • Glutamate carboxypeptidase-II
  • Pharmacokinetics

ASJC Scopus subject areas

  • Analytical Chemistry
  • Pharmaceutical Science
  • Drug Discovery
  • Spectroscopy
  • Clinical Biochemistry

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