Transport, Metabolism, and in Vivo Population Pharmacokinetics of the Chloro Benztropine Analogs, a Class of Compounds Extensively Evaluated in Animal Models of Drug Abuse

Othman, Ahmed A.; Syed, S.; Newman, Amy Hauck; Eddington, Natalie D.

doi:10.1124/jpet.106.111245

Cited by 15 publications

(32 citation statements)

References 29 publications

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“…Consequently, the residual error was fixed to 10.7% based on a sensitivity analysis, and the final selected value was the value resulting in the lowest objective function and the highest precision in estimation of interanimal variability. The 10.7% residual random error was comparable with the estimated or fixed values for previously studied BZT analogs using identical experimental technique (Othman et al, 2007). Figure 3 represents the relevant diagnostic plots for the final population pharmacokinetic model for 3Ј-Cl BZT, and it indicates that the model described the pharmacokinetics of 3Ј-Cl BZT without any systematic bias.…”

Section: Resultssupporting

confidence: 62%

“…The binding model was regressed to the microdialysis data from the two dose levels tested for each drug (data from 10 animals for 3Ј-Cl BZT and 12 animals for 4Ј,4Љ-diCl BZT). Because the plasma concentrations of the BZT analogs were not measured in the same animals in which the microdialysis experiments were conducted, the mean population pharmacokinetic parameters determined in the current study for 3Ј-Cl BZT and in a previous study for 4Ј,4Љ-diCl BZT (Othman et al, 2007) were used to simulate the plasma concentrations for a typical animal at the times of measurement of DA for each dose tested. The plasma concentrations for all the animals were then fixed to these typical values, and they were used as input for the pharmacodynamic modeling.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, several studies focused on characterizing the mechanisms underlying the behavioral differences of the BZT analogs (Campbell et al, 2005;Desai et al, 2005a;Tanda et al, 2005Tanda et al, . 2007Othman et al, 2007). Such characterization could have important implications for successful design of substitute pharmacotherapies for treatment of cocaine abuse that should share the mechanism of action of cocaine without sharing its high abuse potential.…”

mentioning

confidence: 99%

“…Previous pharmacokinetic studies from our laboratory in rats for cocaine, 4Ј-Cl, and 4Ј,4Љ-diCl BZT (Raje et al, 2003;Othman et al, 2007) indicated that 1) the brain uptake of the chloro-analogs was comparable and higher than that of cocaine excluding the extent of brain exposure as a factor mediating the behavioral differences; 2) there was no time delay in brain entry of 4Ј-Cl BZT or 4Ј,4Љ-diCl BZT in comparison with cocaine; and 3) the rank order for the plasma and brain elimination half-lives was the reverse of the differences in abuse liability, i.e., 4Ј,4Љ-diCl BZT Ͼ Ͼ 4Ј-Cl BZT Ͼ cocaine.…”

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confidence: 99%

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Applicability of the Dopamine and Rate Hypotheses in Explaining the Differences in Behavioral Pharmacology of the Chloro-Benztropine Analogs: Studies Conducted Using Intracerebral Microdialysis and Population Pharmacodynamic Modeling

Othman

Newman²,

Eddington³

2007

J Pharmacol Exp Ther

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Previous studies indicated that the chloro-benztropine analogs differed significantly in their cocaine-like activity, which was not expected based on the similarity in their in vitro binding affinity and functional potency at the dopamine transporter (DAT). The present study was designed to extend the understanding of the involvement of both pharmacokinetic and pharmacodynamic factors in mediating the behavioral differences among these analogs. The pharmacokinetics of 3Ј-chloro-3␣-(diphenylmethoxy)tropane (3Ј-Cl BZT), the analog showing a cocaine-like behavioral profile in rodents, was compared with previously reported pharmacokinetic characteristics of cocaine and 4Ј,4Љ-dichloro-3␣-(diphenylmethoxy)tropane (4Ј,4Љ-diCl BZT), an analog totally devoid of cocaine-like actions. Microdialysis studies in rats were conducted to determine whether 3Ј-Cl and 4Ј,4Љ-diCl BZT differed significantly in their effect on nucleus accumbens extracellular dopamine levels, with cocaine serving as a reference. A mechanistic model based on DAT association/ dissociation kinetics was used to describe the time delay between the plasma concentrations of the chloro-analogs and their dopaminergic effects. 3Ј-Cl BZT had plasma elimination half-life of 1.9 h versus 0.5 and 21.1 h for cocaine and 4Ј,4Љ-diCl BZT, respectively. 4Ј,4Љ-diCl BZT increased the DA levels at a slower rate and to a significantly lower extent relative to 3Ј-Cl BZT that were, in turn, lower than cocaine. The duration of dopamine elevation was as follows: 4Ј,4Љ-diCl BZT Ͼ 3Ј-Cl BZT Ͼ cocaine. The model indicated faster association and dissociation with DAT for 3Ј-Cl BZT relative to 4Ј,4Љ-diCl BZT. The present results indicate that behavioral differences among the chloro-analogs may be explainable based on both the dopamine and rate hypotheses of drug abuse.Substantial evidence has accumulated over the years in favor of the dopamine (DA) hypothesis of cocaine abuse (Ritz et al., 1987;Kuhar et al., 1991;Volkow et al., 1997). According to this hypothesis, the ability of cocaine to block the dopamine transporter (DAT) and to inhibit DA uptake, which results in increased dopaminergic neurotransmission in the mesolimbic and mesocortic systems, is the critical element in mediating the reinforcing and psychostimulant effects of cocaine.The benztropine (BZT) analogs are potent and selective DA uptake inhibitors (Newman et al., 1994(Newman et al., , 1995Katz et al., 1999). However, they are generally weak psychostimulants and weak reinforcers relative to cocaine in animal models of drug abuse Woolverton et al., 2001). In addition, the BZT analogs have shown gradations in their cocaine-like activities that are not matched by significant

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Section: Resultssupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Applicability of the Dopamine and Rate Hypotheses in Explaining the Differences in Behavioral Pharmacology of the Chloro-Benztropine Analogs: Studies Conducted Using Intracerebral Microdialysis and Population Pharmacodynamic Modeling

Othman

Newman²,

Eddington³

2007

J Pharmacol Exp Ther

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“…Pharmacokinetic studies have found BZT analogs in brain shortly after injection, with only small differences in central nervous system permeability compared with cocaine (Raje et al, 2003;Othman et al, 2007). Despite this rapid central nervous system availability, Tanda et al (2005) showed slower increases in extracellular dopamine produced by 4-Cl-BZT compared with cocaine.…”

Section: Discussionmentioning

confidence: 99%

Assessment of Reinforcing Effects of Benztropine Analogs and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors

Hiranita¹,

Soto²,

Newman³

et al. 2009

J Pharmacol Exp Ther

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Benztropine (BZT) analogs inhibit dopamine uptake but are less effective than cocaine in producing behavioral effects predicting abuse liability. The present study compared reinforcing effects of intravenous BZT analogs with those of standard monoamine uptake inhibitors and the effects of their oral pretreatment on cocaine self-administration. Responding of rats was maintained by cocaine [0.032-1.0 mg/kg/injection (inj)] or food reinforcement under fixed-ratio five-response schedules. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine or substituted methylphenidate, with lower rates maintained at lower and higher doses. The N-methyl BZT analog, AHN 1-055 (3␣-[bis(4Ј-fluorophenyl)methoxy]-tropane), also maintained responding (0.1 mg/kg/inj), although maximal rates were less than those with cocaine. Responding was not main- citalopram. Presession treatment with methylphenidate (3.2-32 mg/kg) dose-dependently shifted the cocaine self-administration dose-effect curve leftward, whereas nisoxetine and citalopram effects were not significant. An intermediate dose of AHN 1-055 (32 mg/kg) increased responding maintained by low cocaine doses and decreased responding maintained by higher doses. A higher dose of AHN 1-055 completely suppressed cocaine-maintained responding. Both AHN 2-005 and JHW 007 dose-dependently (10 -32 mg/kg) decreased cocaine selfadministration, shifting its dose-effect curve down. Decreases in cocaine-maintained responding occurred at doses of methylphenidate and BZT analogs that left food-maintained responding unchanged. During a component in which injections were not available, methylphenidate and AHN 1-055, but not AHN 2-005 or JHW 007, increased response rates. These findings further support the low abuse liability of BZT analogs and their potential development as medications for cocaine abuse.

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Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy

Maxwell

Nevin

Stahl

et al. 2015

Clinical Case Reports

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Key Clinical MessageSusceptibility to quinoline antimalarial intoxication may reflect individual genetic and drug-induced variation in neuropharmacokinetics. In this report, we describe a case of chloroquine intoxication that appeared to be prolonged by subsequent use of multiple psychotropic medications. This case highlights important new considerations for the management of quinoline antimalarial intoxication.

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Transport, Metabolism, and in Vivo Population Pharmacokinetics of the Chloro Benztropine Analogs, a Class of Compounds Extensively Evaluated in Animal Models of Drug Abuse

Cited by 15 publications

References 29 publications

Applicability of the Dopamine and Rate Hypotheses in Explaining the Differences in Behavioral Pharmacology of the Chloro-Benztropine Analogs: Studies Conducted Using Intracerebral Microdialysis and Population Pharmacodynamic Modeling

Applicability of the Dopamine and Rate Hypotheses in Explaining the Differences in Behavioral Pharmacology of the Chloro-Benztropine Analogs: Studies Conducted Using Intracerebral Microdialysis and Population Pharmacodynamic Modeling

Assessment of Reinforcing Effects of Benztropine Analogs and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors

Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy

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