Abstract
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.
Footnotes
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This research was funded in part by National Institutes of Health/National Institute on Drug Abuse-Intramural Research Program and National Cancer Institute Grant CA87654-02.
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DOI: 10.1124/jpet.103.053504.
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ABBREVIATIONS: DAT, dopamine transporter; BZT, benztropine; BBB, blood-brain barrier; BBMEC, bovine brain microvessel endothelial cell; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; MEM, minimal essential medium; HPLC, high-performance liquid chromatography; A → B, apical-to-basolateral; B → A, basolateral-to-apical; P-gp, P-glycoprotein; Papp, apparent permeability coefficient; AUC, area under the curve.
- Received April 24, 2003.
- Accepted June 11, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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