Pharmacokinetics and pharmacodynamics of the glutamate carboxypeptidase II inhibitor 2-MPPA show prolonged alleviation of neuropathic pain through an indirect mechanism

James J. Vornov, Krystyna M. Wozniak, Ying Wu, Camilo Rojas, Rana Rais, Barbara Slusher

Research output: Contribution to journalArticle

Abstract

Glutamate carboxypeptidase II (GCP II) is a therapeutic target in neurologic disorders associated with excessive activation of glutamatergic systems. The potent, orally bioavailable GCP II inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) is effective in preclinical models of diseases where excess glutamate release is implicated, including neuropathic pain, and was the first GCP II inhibitor to be administered to man. The relationships between dosing regimen, pharmacokinetics, and analgesia in a neuropathic pain model were examined in rats to aid development of clinical dosing. The efficacy of oral 2-MPPA in the chronic constrictive injury model was not simply related to plasma concentrations. Even though maximal concentrations were observed within 1 hour of dosing, the analgesic effect took at least 8 days of daily dosing to become significant. The delay was not due to tissue drug accumulation since inhibitory concentrations of the drug were achieved in the nerve within 1 hour of dosing. There was also no accumulation of drug in plasma or tissue after multiple daily dosing. Effects were dependent on reaching a threshold concentration since dividing the daily dose led to a loss of effect. The analgesic effect outlasted plasma exposure and was maintained for days even after daily dosing was halted. The delayed onset, dependence on threshold plasma concentration, and sustained effects after exposure support the hypothesis that an indirect, long-lived mechanism of action exists. Although these longer lasting secondary mechanisms are not yet identified, daily clinical dosing of a GCP II inhibitor seems justified.

Original languageEnglish (US)
Pages (from-to)406-413
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume346
Issue number3
DOIs
StatePublished - Sep 2013

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Glutamate Carboxypeptidase II
Neuralgia
Pharmacokinetics
Analgesics
Pharmaceutical Preparations
Nervous System Diseases
Analgesia
Glutamic Acid
2-(3-mercaptopropyl)pentanedioic acid
Wounds and Injuries

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

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title = "Pharmacokinetics and pharmacodynamics of the glutamate carboxypeptidase II inhibitor 2-MPPA show prolonged alleviation of neuropathic pain through an indirect mechanism",
abstract = "Glutamate carboxypeptidase II (GCP II) is a therapeutic target in neurologic disorders associated with excessive activation of glutamatergic systems. The potent, orally bioavailable GCP II inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) is effective in preclinical models of diseases where excess glutamate release is implicated, including neuropathic pain, and was the first GCP II inhibitor to be administered to man. The relationships between dosing regimen, pharmacokinetics, and analgesia in a neuropathic pain model were examined in rats to aid development of clinical dosing. The efficacy of oral 2-MPPA in the chronic constrictive injury model was not simply related to plasma concentrations. Even though maximal concentrations were observed within 1 hour of dosing, the analgesic effect took at least 8 days of daily dosing to become significant. The delay was not due to tissue drug accumulation since inhibitory concentrations of the drug were achieved in the nerve within 1 hour of dosing. There was also no accumulation of drug in plasma or tissue after multiple daily dosing. Effects were dependent on reaching a threshold concentration since dividing the daily dose led to a loss of effect. The analgesic effect outlasted plasma exposure and was maintained for days even after daily dosing was halted. The delayed onset, dependence on threshold plasma concentration, and sustained effects after exposure support the hypothesis that an indirect, long-lived mechanism of action exists. Although these longer lasting secondary mechanisms are not yet identified, daily clinical dosing of a GCP II inhibitor seems justified.",
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