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.
OBJECTIVE
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 ( approximately 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.
Raje
Sangeeta
S
Pharmacokinetics Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, 21201-6808, USA.
Cornish
Jennifer
J
Newman
Amy H
AH
Cao
Jianjing
J
Katz
Jonathan L
JL
Eddington
Natalie D
ND
D000818:Animals; D001590:Benztropine / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D003042:Cocaine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D004347:Drug Interactions; D020128:Inhibitory Concentration 50; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D050483:Dopamine Plasma Membrane Transport Proteins; C464560:N-methyl-3-(bis(4'-fluorophenyl)methoxy)tropane; D001590:Benztropine; D003042:Cocaine