Microdialysis Evaluation of Clozapine and <i>N</i>-Desmethylclozapine Pharmacokinetics in Rat Brain

Cremers, Thomas; Flik, Gunnar; Hofland, Corry M.; Stratford, Robert E.

doi:10.1124/dmd.112.045682

Cited by 27 publications

(23 citation statements)

References 31 publications

(37 reference statements)

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“…In rats, 10 mg/kg clozapine (s.c.) leads to a peak unbound plasma level from intracranial microdialysis sampling of ∼0.07 µ m , and a delayed peak level of 0.008 µ m N -Des (Cremers et al, 2012). At this dose, clozapine has been shown to reduce amphetamine hyperlocomotion (Natesan et al, 2007) and reduces the ASR in rats (Conti et al, 2005; Feifel et al, 2011), just as we observed after CNO administration.…”

Section: Discussionmentioning

confidence: 99%

Clozapine N-Oxide Administration Produces Behavioral Effects in Long–Evans Rats: Implications for Designing DREADD Experiments

MacLaren

Browne

Shaw

et al. 2016

eNeuro

314

247

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Clozapine N-oxide (CNO) is a ligand for a powerful chemogenetic system that can selectively inhibit or activate neurons; the so-called Designer Receptors Exclusively Activated by Designer Drugs (DREADD) system. This system consists of synthetic G-protein-coupled receptors, which are not believed to be activated by any endogenous ligand, but are activated by the otherwise inert CNO. However, it has previously been shown that the administration of CNO in humans and rats leads to detectable levels of the bioactive compounds clozapine and N-desmethylclozapine (N-Des). As a follow-up, experiments were conducted to investigate the effects of CNO in male Long–Evans rats. It was found that 1 mg/kg CNO reduced the acoustic startle reflex but had no effect on prepulse inhibition (PPI; a measure of sensorimotor gating). CNO (2 and 5 mg/kg) had no effect on the disruption to PPI induced by the NMDA antagonist phencyclidine or the muscarinic antagonist scopolamine. In locomotor studies, CNO alone (at 1, 2, and 5 mg/kg) had no effect on spontaneous locomotion, but 5 mg/kg CNO pretreatment significantly attenuated d-amphetamine-induced hyperlocomotion. In line with the behavioral results, fast-scan cyclic voltammetry found that 5 mg/kg CNO significantly attenuated the d-amphetamine-induced increase in evoked dopamine. However, the effects seen after CNO administration cannot be definitively ascribed to CNO because biologically relevant levels of clozapine and N-Des were found in plasma after CNO injection. Our results show that CNO has multiple dose-dependent effects in vivo and is converted to clozapine and N-Des emphasizing the need for a CNO-only DREADD-free control group when designing DREADD-based experiments.

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Section: Discussionmentioning

confidence: 99%

Clozapine N-Oxide Administration Produces Behavioral Effects in Long–Evans Rats: Implications for Designing DREADD Experiments

MacLaren

Browne

Shaw

et al. 2016

eNeuro

314

247

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“…To get the maximal therapeutic window of drugs, clozapine at 100 mg/kg was chosen to investigate the drug-drug interaction effects of rhein on the PK and PD of clozapine in rat brain. Although studies of clozapine and norclozapine PK in the rat mPFC by in vivo microdialysis and HPLC-MS/MS have been reported (Cremers et al, 2012;Li et al, 2014), there are no studies of drug-drug interactions of rhein on clozapine PK in the rat mPFC. Thus, the PK of clozapine and norclozapine in rat mPFC was conducted by in vivo microdialysis in conscious rats.…”

Section: Discussionmentioning

confidence: 99%

“…The use of ionpair high-performance liquid chromatography-electrochemical detection (HPLC-ECD) is of great interest for the determination of monoamine neurotransmitters [i.e., norepinephrine; epinephrine; 3,4-dihydroxyphenylacetic acid (DOPAC); DA; 5-hydroxyindole-3-acetic acid (5-HIAA); homovanillic acid (HVA); 5-HT; and 3-methoxytyramine hydrochloride] in microdialysis samples (Bicker et al, 2013). Moreover, ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been used to quantify the concentrations of drug and its metabolites in microdialysate (Cremers et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

The Drug-Drug Effects of Rhein on the Pharmacokinetics and Pharmacodynamics of Clozapine in Rat Brain Extracellular Fluid by In Vivo Microdialysis

Hou

Lin

et al. 2015

J Pharmacol Exp Ther

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Clozapine, an atypical antipsychotic agent, is highly effective in treatment-resistant schizophrenia; however, its major side effect is constipation. Instead of laxatives, rhein is a pharmacologically active component found in Rheum palmatum L., a medicinal herbal remedy for constipation. The purpose of this study is to determine whether rhein impacts the pharmacokinetics (PK) and pharmacodynamics (PD) of clozapine in brain when used to relieve clozapine-induced constipation. Here, we have investigated not only the PK of clozapine in blood but also the effects of rhein on the PK of clozapine in blood and in brain extracellular fluid together with the PD effects on neurotransmitters in extracellular fluid. The concentrations of clozapine and norclozapine in biologic samples were measured by ultra-performance liquid chromatography-tandem mass spectrometry. The drug-drug effects of rhein on extracellular neurotransmitter efflux in the rat medial prefrontal cortex (mPFC) produced by clozapine were assayed by highperformance liquid chromatography-electrochemical detection. The results demonstrate that the clozapine PK was nonlinear. Pretreatment with rhein for 7 days increased the total blood concentration of clozapine, but significantly reduced the unbound clozapine concentrations in the mPFC by approximately 3-fold. Furthermore, 7 days of rhein pretreatment thoroughly abolished the efflux of dopamine and its metabolite (3,4-dihydroxyphenylacetic acid) and altered the profile of homovanillic acid, another metabolite of dopamine, in the mPFC. In conclusion, rhein was found to substantially decrease clozapine and norclozapine concentrations in the mPFC dialysate, and this is accompanied by lower concentrations in the neurotransmitters in the same biophase. These findings suggest that a detailed clinical study for drug-drug interactions is recommended.

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“…The 6-fold higher unbound brain ECF concentrations seen for oxycodone compared to morphine were proposed to explain this phenomenon, and modelling of these concentrations supported this theory, as demonstrated by a higher uptake clearance than efflux clearance across the BBB for oxycodone, while the reverse result was obtained for morphine (43). Another example of application-based modelling for CNS drugs was presented by Cremers et al (44) for the anti-psychotic drug clozapine and its active human metabolite Ndesmethylclozapine. The highly variable response to clozapine treatment in patients with schizophrenia is thought to be due to inter-patient variability in ECF concentrations, for the same plasma concentrations.…”

Section: Compartmental Pk Modelsmentioning

confidence: 96%

Physiologically Based Pharmacokinetic Modelling of Drug Penetration Across the Blood–Brain Barrier—Towards a Mechanistic IVIVE-Based Approach

Ball

Bouzom

Scherrmann

et al. 2013

AAPS J

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Predicting the penetration of drugs across the human blood-brain barrier (BBB) is a significant challenge during their development. A variety of in vitro systems representing the BBB have been described, but the optimal use of these data in terms of extrapolation to human unbound brain concentration profiles remains to be fully exploited. Physiologically based pharmacokinetic (PBPK) modelling of drug disposition in the central nervous system (CNS) currently consists of fitting preclinical in vivo data to compartmental models in order to estimate the permeability and efflux of drugs across the BBB. The increasingly popular approach of using in vitro-in vivo extrapolation (IVIVE) to generate PBPK model input parameters could provide a more mechanistic basis for the interspecies translation of preclinical models of the CNS. However, a major hurdle exists in verifying these predictions with observed data, since human brain concentrations can't be directly measured. Therefore a combination of IVIVE-based and empirical modelling approaches based on preclinical data are currently required. In this review, we summarise the existing PBPK models of the CNS in the literature, and we evaluate the current opportunities and limitations of potential IVIVE strategies for PBPK modelling of BBB penetration.

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Microdialysis Evaluation of Clozapine and N-Desmethylclozapine Pharmacokinetics in Rat Brain

Cited by 27 publications

References 31 publications

Clozapine N-Oxide Administration Produces Behavioral Effects in Long–Evans Rats: Implications for Designing DREADD Experiments

Clozapine N-Oxide Administration Produces Behavioral Effects in Long–Evans Rats: Implications for Designing DREADD Experiments

The Drug-Drug Effects of Rhein on the Pharmacokinetics and Pharmacodynamics of Clozapine in Rat Brain Extracellular Fluid by In Vivo Microdialysis

Physiologically Based Pharmacokinetic Modelling of Drug Penetration Across the Blood–Brain Barrier—Towards a Mechanistic IVIVE-Based Approach

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