Receptor Occupancy and Brain Free Fraction

Watson, Jeannette M.; Wright, S. M.; Lucas, A.; Clarke, Kirsten; Viggers, Jean; Cheetham, Sharon C.; Jeffrey, Philip; Porter, Rod A.; Read, Kevin D.

doi:10.1124/dmd.108.022814

Cited by 110 publications

(67 citation statements)

References 13 publications

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“…There are several reports based on Mdr1a KO models demonstrating that Pgp reduces risperidone uptake into the brains of both mice (Wang et al, 2004;Doran et al, 2005;Summerfield et al, 2006) and rats (Bundgaard et al, 2012). Using plasma and brain homogenate free fraction analysis, efflux asymmetry was observed in mice (Mau- (Watson et al, 2009). In a study involving direct measurement by microdialysis of risperidone in brain ECF of rats and comparison to unbound plasma concentrations after intravenous infusion over 6 h, Liu et al (2009) reported a risperidone steady-state ECF-to-plasma ,u ratio of 0.53.…”

Section: Compartmental Pk Parameter Estimates Based On Simultaneous Fmentioning

confidence: 99%

“…In Mdr1a mouse KO studies , clozapine brain concentrations were increased in KO relative to WT animals, but the drug was unlike risperidone in strongly differentiating as a Pgp substrate. In addition, no support for clozapine net efflux asymmetry was obtained using plasma and brain free fraction analysis in mice (Maurer et al, 2005) or rats (Watson et al, 2009). Clinical studies have shown a relationship between Mdr1a polymorphisms and efficacious clozapine systemic exposure (Jaquenoud Sirot et al, 2009;Consoli et al, 2009).…”

Section: Compartmental Pk Parameter Estimates Based On Simultaneous Fmentioning

confidence: 99%

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

et al. 2012

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ABSTRACT:A significant barrier to realization of the full potential of clozapine as a therapeutic agent in the treatment of schizophrenia is the substantial interpatient variability that exists along the therapeutic continuum of no response-efficacious response-adverse response. Genetic polymorphisms that manifest as highly variable pharmacodynamic and pharmacokinetic measures are its expected causes. To support investigations that seek to understand these causes, the plasma and central nervous system pharmacokinetics of clozapine were determined in rats, the latter using microdialysis sampling. Results obtained with clozapine and Ndesmethylclozapine, a pharmacologically active human metabolite that was administered to a separate group of animals, support a conclusion of net carrier-mediated efflux of both compounds across the blood-brain barrier. These results are supported by the replication of published findings regarding the passive transport and net efflux transport of two model compounds, escitalopram and risperidone, respectively. The results obtained with clozapine and N-desmethylclozapine are considered a first step in the development of preclinical pharmacokinetic-pharmacodynamic models that will support deeper mechanistic studies of clozapine in in vivo pharmacology, as well as the development of translational models that augment pharmacogenetic investigations that seek to improve the safety and efficacy of clozapine therapeutic intervention in the treatment of schizophrenia.

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Section: Compartmental Pk Parameter Estimates Based On Simultaneous Fmentioning

confidence: 99%

Section: Compartmental Pk Parameter Estimates Based On Simultaneous Fmentioning

confidence: 99%

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

et al. 2012

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“…Therefore, total brain concentration does not represent the drug concentration at the biophase. Although the scientific rationale for the free drug hypothesis is very strong, there are limited data in the literature to actually prove that the unbound brain concentration, not the total brain tissue concentration, determines CNS activity (Cox et al, 1998;Kalvass et al, 2007b;Watson et al, 2009). Because of the lack of extensive well documented data in the literature and the lack of understanding of novel drug targets in most drug discovery and development programs, sometimes it is debatable whether the unbound brain concentration or the total brain concentration determines in vivo activity.…”

mentioning

confidence: 99%

Unbound Brain Concentration Determines Receptor Occupancy: A Correlation of Drug Concentration and Brain Serotonin and Dopamine Reuptake Transporter Occupancy for Eighteen Compounds in Rats

Liu

Vilenski²,

Kwan³

et al. 2009

Drug Metab Dispos

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ABSTRACT:It is a commonly accepted hypothesis that central nervous system (CNS) activity is determined by the unbound brain drug concentration. However, limited experimental data are available in the literature to support this hypothesis. The objective of this study was to test this hypothesis by examining the relationship between in vitro binding affinity (K I ) and in vivo activity quantified as the drug concentration occupying 50% of the transporters (OC 50 ) for 18 serotonin (SERT) and dopamine transporter (DAT) inhibitors. In vivo rat OC 50 was determined by autoradiography using In the present study, a 10-fold improvement was also observed by using the unbound plasma concentration rather than the total plasma concentration to predict the biophase concentration in the brain. This study supports the hypothesis that CNS activity is more accurately determined by the unbound brain drug concentration and not by the total brain drug concentration.

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“…This is because of factors related to CSF turnover, intrabrain diffusion, extra-intracellular exchange, and qualitative and quantitative differences in BBB and blood-CSF-barrier transport mechanisms. Because many targets (receptors) face the brain extracellular fluid (ECF), brain ECF concentrations are anticipated to reflect target site concentrations best and will therefore provide a better basis to describe PK and pharmacodynamic (PD) relations in a more mechanistic manner (Del Bigio, 1995;de Lange et al, 1999de Lange et al, , 2005de Lange and Danhof, 2002;Watson et al, 2009;Jeffrey and Summerfield, 2010).…”

Section: Introductionmentioning

confidence: 99%

Systemic and Direct Nose-to-Brain Transport Pharmacokinetic Model for Remoxipride after Intravenous and Intranasal Administration

Stevens¹,

Ploeger²,

Graaf³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Intranasal (IN) administration could be an attractive mode of delivery for drugs targeting the central nervous system, potentially providing a high bioavailability because of avoidance of a hepatic first-pass effect and rapid onset of action. However, controversy remains whether a direct transport route from the nasal cavity into the brain exists. Pharmacokinetic modeling is proposed to identify the existence of direct nose-to-brain transport in a quantitative manner. The selective dopamine-D2 receptor antagonist remoxipride was administered at different dosages, in freely moving rats, by the IN and intravenous (IV) route. Plasma and brain extracellular fluid (ECF) concentration-time profiles were obtained and simultaneously analyzed using nonlinear mixed-effects modeling. Brain ECF/plasma area under the curve ratios were 0.28 and 0.19 after IN and IV administration, respectively. A multicompartment pharmacokinetic model with two absorption compartments (noseto-systemic and nose-to-brain) was found to best describe the observed pharmacokinetic data. Absorption was described in terms of bioavailability and rate. Total bioavailability after IN administration was 89%, of which 75% was attributed to direct nose-to brain transport. Direct nose-to-brain absorption rate was slow, explaining prolonged brain ECF exposure after IN compared with IV administration. These studies explicitly provide separation and quantitation of systemic and direct nose-to-brain transport after IN administration of remoxipride in the rat. Describing remoxipride pharmacokinetics at the target site (brain ECF) in a semiphysiology-based manner would allow for better prediction of pharmacodynamic effects.

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Receptor Occupancy and Brain Free Fraction

Cited by 110 publications

References 13 publications

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

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

Unbound Brain Concentration Determines Receptor Occupancy: A Correlation of Drug Concentration and Brain Serotonin and Dopamine Reuptake Transporter Occupancy for Eighteen Compounds in Rats

Systemic and Direct Nose-to-Brain Transport Pharmacokinetic Model for Remoxipride after Intravenous and Intranasal Administration

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