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Investigation of the potential pharmacokinetic and pharmaco‐dynamic drug interaction between AHN 1‐055, a potent benztropine analog used for cocaine abuse, and cocaine after dosing in rats using intracerebral microdialysis
Author(s) -
Raje Sangeeta,
Cornish Jennifer,
Newman Amy H.,
Cao Jianjing,
Katz Jonathan L.,
Eddington Natalie D.
Publication year - 2006
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.497
Subject(s) - benztropine , microdialysis , pharmacokinetics , pharmacology , chemistry , dopamine transporter , dopamine , cocaine dependence , nucleus accumbens , norepinephrine transporter , dopamine uptake inhibitors , tropane , medicine , dopaminergic , norepinephrine , stereochemistry , addiction , psychiatry
Purpose . AHN 1‐055, a benztropine (BZT) analog, binds with high affinity to the dopamine transporter (DAT), possesses behavioral, pharmacokinetic (PK) and brain microdialysate dopamine (DA) profiles distinct from cocaine. Accordingly, the objectives of this study were to evaluate the pharmacokinetics and dopamine release of AHN 1‐055, in the presence of cocaine. Methods . Male Sprague Dawley rats (∼300 g) were administered 5 mg/kg of AHN 1‐055 and cocaine i.v. and blood and brain samples were collected over 36 h. In addition, dialysis probes were stereotaxically implanted into the nucleus accumbens and extracellular fluid (ECF) DA levels were measured. PK and PD models were used to describe the relationship between the AHN 1‐055, cocaine and DA levels. Results . No significant ( p <0.05) differences were found in the PK parameters of AHN 1‐055 alone ( V dss =18.7 l/kg, Cl =1.8 l/h/kg and t 1/2 =7.69 h) or AHN 1‐055 with cocaine ( V dss =17.4 l/kg, Cl =1.9 l/h/kg and t 1/2 =6.82 h). The brain‐to‐plasma (B/P) ratios (B/P AHN 1−055 =4.8 vs B/P with cocaine =4.4) and half‐lives ( t 1/2(AHN 1−055) =6.2 h vs t 1/2(cocaine)= 5.6 h for AHN 1‐055 alone and with cocaine were comparable. AHN 1‐055 DA profiles were significantly different after co‐administration with cocaine. There were no differences in the IC 50 for AHN 1‐055, with cocaine, however, the IC 50 for cocaine was significantly reduced with AHN 1‐055. Conclusions . The PK parameters of AHN 1‐055 were not changed, however, the effect on DA levels was affected when cocaine was administered with AHNDA profile is affected when dosed with cocaine. This latter effect is a desirable attribute in the development of a medication as a potential substitute therapeutic medication for the treatment of cocaine abuse. Copyright © 2006 John Wiley & Sons, Ltd.