The potent glutamate carboxypeptidase II (GCP II) inhibitor 2-MPPA [2-(3-mercaptopropyl) pentanedioic acid] is effective in preclinical models of disease where excessive glutamate release is implicated. The relationship between pharmacokinetics and analgesia in a neuropathic pain model was examined in rats. 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. 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 concentrations, and sustained effects without maintaining exposure support the hypothesis that an indirect, long-lived mechanism of action exists.
See article at J Pharmacol Exp Ther 2013, 346:406–413.
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