TY - JOUR
T1 - Bioanalytical method for evaluating the pharmacokinetics of the GCP-II inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA)
AU - Rais, Rana
AU - Rojas, Camilo
AU - Wozniak, Krystyna
AU - Wu, Ying
AU - Zhao, Ming
AU - Tsukamoto, Takashi
AU - Rudek, Michelle A.
AU - Slusher, Barbara S.
N1 - Funding Information:
This study was supported by NIH grant # RO1CA161056 and the Johns Hopkins Brain Science Institute . This project was also supported in part by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University (NIH grants P30 CA006973 and UL1 RR025005 ) and the Shared Instrument Grant ( 1S10RR026824-01 ).
PY - 2014/1/25
Y1 - 2014/1/25
N2 - 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.
AB - 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.
KW - 2-PMPA
KW - Brain/plasma ratio
KW - Derivatization
KW - Glutamate carboxypeptidase-II
KW - Pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=84884220816&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884220816&partnerID=8YFLogxK
U2 - 10.1016/j.jpba.2013.08.028
DO - 10.1016/j.jpba.2013.08.028
M3 - Article
C2 - 24055700
AN - SCOPUS:84884220816
SN - 0731-7085
VL - 88
SP - 162
EP - 169
JO - Journal of Pharmaceutical and Biomedical Analysis
JF - Journal of Pharmaceutical and Biomedical Analysis
ER -