PT  - JOURNAL ARTICLE
AU  - Rana Rais
AU  - Randall Hoover
AU  - Krystyna Wozniak
AU  - Michelle A. Rudek
AU  - Takashi Tsukamoto
AU  - Jesse Alt
AU  - Camilo Rojas
AU  - Barbara S. Slusher
TI  - Reversible Disulfide Formation of the Glutamate Carboxypeptidase II Inhibitor E2072 Results in Prolonged Systemic Exposures In Vivo
AID  - 10.1124/dmd.112.046821
DP  - 2012 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 2315--2323
VI  - 40
IP  - 12
4099  - http://dmd.aspetjournals.org/content/40/12/2315.short
4100  - http://dmd.aspetjournals.org/content/40/12/2315.full
SO  - Drug Metab Dispos2012 Dec 01; 40
AB  - E2072 [(3-2-mercaptoethyl)biphenyl-2,3′-dicarboxylic acid] is a novel, potent and selective thiol-based glutamate carboxypeptidase II (GCP-II) inhibitor that has shown robust analgesic and neuroprotective efficacy in preclinical models of neuropathic pain and chemotherapy-induced peripheral neuropathy. For the first time, we describe the drug metabolism and pharmacokinetic profile of E2072 in rodents and primates. Intravenously administered E2072 was found to exhibit an unexpectedly long terminal half-life (105 ± 40 h) in rats. The long half-life was found to be the result of its ability to rapidly form reversible homo- and possibly heterodisulfides that served as a continuous E2072 depot. The half-life of reversible homodisulfides was 208 ± 81 h. In further support, direct intravenous administration of the E2072-homodisulfide in rats resulted in the formation of E2072, with both E2072 and its disulfide detected in plasma up to 7 days after dose. The observed long exposures were consistent with the sustained efficacy of E2072 in rodent pain models for several days after dose cessation. It is noteworthy that a shorter t1/2 of E2072 (23.0 ± 1.2 h) and its homodisulfide (21.0 ± 0.95 h) was observed in primates, indicating interspecies differences in its disposition. In addition, E2072 was found to be orally available with an absolute bioavailability of ∼30% in rats and ∼39% in monkeys. A tissue distribution study of E2072 and its homodisulfide in rats showed good tissue penetration, particularly in sciatic nerve, the presumed site of action for treatment of neuropathy. Metabolic stability and the correlation between pharmacokinetic profile and pharmacological efficacy support the use of this GCP-II inhibitor in the clinic.