TY - JOUR T1 - Evaluation of the Blood-Brain Barrier Transport, Population Pharmacokinetics, and Brain Distribution of Benztropine Analogs and Cocaine Using in Vitro and in Vivo Techniques JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 801 LP - 808 DO - 10.1124/jpet.103.053504 VL - 307 IS - 2 AU - Sangeeta Raje AU - Jianjing Cao AU - Amy Hauck Newman AU - Huanling Gao AU - Natalie D. Eddington Y1 - 2003/11/01 UR - http://jpet.aspetjournals.org/content/307/2/801.abstract N2 - The N-substituted 3α-[bis(4′-fluorophenyl)methoxy]tropanes (AHN 2-003, AHN 1-055, AHN 2-005, and JHW 007) bind with high affinity to the dopamine transporter and inhibit dopamine uptake more potently than cocaine, but they demonstrate behavioral profiles in animal models of psychostimulant abuse that are unlike that of cocaine. The objective of this study was to characterize the in vitro permeability, brain distribution, and pharmacokinetics of the benztropine (BZT) analogs. Transport studies of cocaine and the BZT analogs (10-4 M) were conducted across bovine brain microvessel endothelial cells. Male Sprague-Dawley rats (∼300 g) were administered BZT analogs (10 mg/kg) or cocaine (5 mg/kg) via the tail vein. Blood and brain samples were collected over 36 h and assayed using UV-high-performance liquid chromatography. Transport of both AHN 1-055 (2.15 × 10-4 cm/s) and JHW 007 (2.83 × 10-4 cm/s) was higher (p < 0.05) than that of cocaine (1.63 × 10-4 cm/s). The volume of distribution (12.3-30.5 l/kg) of the analogs was significantly higher than cocaine (0.9 l/kg). The BZT analogs displayed a ≥8-fold higher elimination half-life (4.12-16.49 h) compared with cocaine (0.49 h). The brain-to-plasma partition coefficients were at least two-fold higher for the BZTs versus cocaine, except for AHN 2-003. The BZT analogs are highly permeable across the blood-brain barrier and possess a pharmacokinetic profile different from that of cocaine. These characteristics, in addition to their distinctive behavioral profiles, suggest that the BZT analogs may be promising candidates for the treatment of cocaine abuse. The American Society for Pharmacology and Experimental Therapeutics ER -