Investigation of the potential pharmacokinetic and pharmacodynamic drug interaction between AHN 1-055, a potent benztropine analog used for cocaine abuse, and cocaine after dosing in rats using intracerebral microdialysis

Sangeeta Raje, Jennifer Cornish, Amy H. Newman, Jianjing Cao, Jonathan L. Katz, Natalie D. Eddington*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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 (Vdss=18.71/kg, Cl=1.81/h/kg and t1/ 2=7.69h) or AHN 1-055 with cocaine (Vdss=17.41/kg, Cl=1.91/h/kg and t1/2=6.82 h). The brain-to-plasma (B/P) ratios (B/PAHN 1-055=4.8 vs B/Pwith cocaine=4.4) and half-lives (t1/ 2(AHN 1-055)=6.2 h vs t1/2(cocaine)=5.6 h for AHN 1-055 alone and with cocaine were comparable. AHN 1-055 DA profiles were significantly different after coadministration with cocaine. There were no differences in the IC50 for AHN 1-055, with cocaine, however, the IC50 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.

Original languageEnglish
Pages (from-to)229-240
Number of pages12
JournalBiopharmaceutics and Drug Disposition
Volume27
Issue number5
DOIs
Publication statusPublished - Jul 2006
Externally publishedYes

Keywords

  • Benztropine analogs
  • Cocaine
  • Dopamine transporter
  • Drug interaction
  • Pharmacokinetics-pharmacodynamics

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