Abstract
Recently, extensive behavioral research has been conducted on the benztropine (BZT) analogs with the goal of developing successful therapeutics for cocaine abuse. The present study was conducted to characterize the contribution of dispositional factors in mediating the behavioral differences among the chloro BZT analogs and to identify cytochrome P450 enzymes involved in their metabolism. Bidirectional transport and efflux studies of four of the chloro BZT analogs were conducted. Screening with a panel of human and rat Supersomes was performed for 4′,4″-diCl BZT. In addition, pharmacokinetic and brain distribution studies for 4′-Cl and 4′,4″-diCl BZT in Sprague-Dawley rats were conducted. The permeability of the chloro analogs ranged from 8.26 to 32.23 and from 1.37 to 21.65 × 10–6 cm/s, whereas the efflux ratios ranged from 2.1 to 6.9 and from 3.3 to 28.4 across Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) and Caco-2 monolayers, respectively. The P-glycoprotein (P-gp) inhibitor verapamil reduced the efflux ratios and enhanced the absorptive transport of the chloro BZT analogs. 4′,4″-diCl BZT was a substrate of human CYP2D6 and 2C19 and rat 2C11 and 3A1. The brain uptake for 4′-Cl and 4′,4″-diCl BZT was comparable and higher than previously reported for cocaine (brain-to-plasma partition coefficient = 4.6–4.7 versus 2.1 for cocaine). The rank order for t1/2 was 4′,4″-diCl BZT ≫ 4′-Cl BZT > cocaine and for steady-state volume of distribution was 4′-Cl BZT > 4′,4″-diCl BZT ≫ cocaine. In conclusion, the chloro analogs differ significantly in their clearance and duration of action, which correlates to their behavioral profiles and abuse liability. Furthermore, these results suggest that the distinctive behavioral profile of these analogs is not due to limited brain exposure.
Footnotes
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This work was supported by National Institutes of Health Grant R01 DA16715-03 from the National Institute on Drug Abuse–Intramural Research Program.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.111245.
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ABBREVIATIONS: DAT, dopamine transporter; BZT, benztropine; 4′-Cl BZT, 4′-chloro-3α-(diphenylmethoxy)tropane; 4′,4″-diCl BZT, 4′,4″-dichloro-3α-(diphenylmethoxy)tropane; 3′-Cl BZT, 3′-chloro-3α-(diphenylmethoxy)tropane; 3′,4″-diCl BZT, 3′,4″-dichloro-3α-(diphenylmethoxy)tropane; P-gp, P-glycoprotein; MDR, multidrug resistance; PBS, phosphate-buffered saline; HPLC, high-performance liquid chromatography; TEER, transepithelial electrical resistance; A-B, apical to basolateral; B-A, basolateral to apical; ANOVA, analysis of variance; AUC, area under the curve; Papp, apparent permeability coefficient; Ri, brain-to-plasma partition coefficient; CL, clearance; Vc, volume of the central compartment; Vp, volume of the peripheral compartment; Q, intercompartmental clearance; IAV, interanimal variability; Vss, steady-state volume of distribution; DA, dopamine; BBB, blood brain barrier; JHW 007, N-(n-butyl)-(bis-fluorophenyl)methoxytropane; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl-2H-tetrazolium, inner salt; XTT, 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide.
- Received July 20, 2006.
- Accepted September 25, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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