Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2487423 | Journal of Pharmaceutical Sciences | 2008 | 18 Pages |
Abstract
GA2â50 is a novel Nâsubstituted benztropine analog with improved potency and selectivity for the dopamine transporter. The pharmacokinetic and pharmacodynamic properties of GA2â50 were characterized as a part of its preclinical evaluation as a substitute medication for cocaine abuse. In vitro transport and metabolism studies as well as pharmacokinetic studies in rats were conducted. Effect of GA2â50 on the extracelluar nucleus accumbens (NAc) dopamine levels and on cocaine's induced dopamine elevation was evaluated using intracerebral microdialysis. GA2â50 showed high transcellular permeability despite being a Pâglycoprotein substrate. GA2â50 was a substrate of human CYP2D6, CYP2C19, CYP2E1, rat CYP2C11, CYP2D1, CYP3A1, and CYP1A2; with low intrinsic clearance values. In vivo, GA2â50 showed high brain uptake (Riââ¼â10), large volume of distribution (Vssâ=â37 L/kg), and long elimination halfâlife (t½â=â19 h). GA2â50 resulted in 1.6â and 2.7âfold dopamine elevation at the 5 and 10 mg/kg i.v. doses. Dopamine elevation induced by GA2â50 was significantly reduced, slower and longer lasting than previously observed for cocaine. GA2â50 had no significant effect on cocaine's induced dopamine elevation upon simultaneous administration. Results from the present study indicate that GA2â50 possesses several attributes sought after for a substitute medication for cocaine abuse. © 2008 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci
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Authors
Ahmed A. Othman, Amy H. Newman, Natalie D. Eddington,