Strategies to assess blood–brain barrier penetration

Di, Li; Kerns, Edward H.; Carter, Guy T.

doi:10.1517/17460441.3.6.677

Cited by 103 publications

(86 citation statements)

References 46 publications

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“…Likewise, brain tissue binding has been routinely determined in multiple species to account for any potential species dependence. However, brain tissue has very different composition than plasma; brain has much higher lipid contents (11% lipid and 7.9% protein) than plasma (0.65% lipid and 18% protein) (Jeffrey and Summerfield, 2007;Di et al, 2008). Likewise, binding to brain tissue is different from binding to plasma tissue.…”

Section: Introductionmentioning

confidence: 99%

Species Independence in Brain Tissue Binding Using Brain Homogenates

Umland²,

Chang³

et al. 2011

Drug Metab Dispos

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148

120

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Section: Introductionmentioning

confidence: 99%

Species Independence in Brain Tissue Binding Using Brain Homogenates

Umland²,

Chang³

et al. 2011

Drug Metab Dispos

Self Cite

148

120

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“…Generally, low brain penetration can be due to low bloodbrain barrier permeability, P-gp efflux, or high plasma protein binding (Di et al, 2008). The major difference between microdialysis and conventional blood sampling is that only the unbound compound can be determined.…”

Section: Discussionmentioning

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 donor plate was placed on the top of the acceptor plate to create a sandwich. The assembly was incubated for different time intervals (2,5,8,16 and 24 hours) at 25°C. After completion of incubation, the sandwich was disassembled and the acceptor solutions were transferred to a 96-well UV transparent plates (Corning) and the concentration of the drugs was measured spectrophotometrically (Spectramax 190; Molecular Device Corporation, California, USA) at the wavelength most appropriate for each drug.…”

Section: Pampa-pbl Procedurementioning

confidence: 99%

“…Effect of time on permeability: Diffusion of the tested compounds in the 96 well plate, from the donor to acceptor compartments for the PAMPA-PBL and PAMPA-Phosphatidylcholine lipid assays was monitored at various time points (2,5,8,16, 24 hours). Drugs were added to 96 well plates in three replicates for a set time points.…”

Section: Pampa-phosphatidylcholine Lipid Procedurementioning

confidence: 99%

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Optimization and Validation of an In Vitro Blood Brain Barrier Permeability Assay Using Artificial Lipid Membrane

Jhala¹

2012

JBB

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Blood-Brain Barrier (BBB) is one of the key issues in the pharmaceutical industry since the Central Nervous System (CNS) drugs need to penetrate the barrier, while the peripherally acting drugs should be impaired in the passage. Most of the CNS drugs enter the brain by transcellular passive diffusion mechanism due to the presence of zonula occludens and limited transport pathways. In the present study two different in-vitro methods to predict BBB permeability of drugs were compared and evaluated. We focused our attention on the effect of time on the permeability in PAMPA model to maximize the high through put nature by decreasing the incubation time. Moreover, we have compared the permeability of 16 structurally diverse, commercially available drugs assessed in two different PAMPA models: (1) a PAMPA-PBL (Porcine brain lipid) (2) a PAMPA-Phosphatidylcholine lipid. Both the models successfully identify CNS+ (High brain penetration) and CNS-(Low brain penetration) drugs. A comparison of the permeability by plotting P app values from both methods allows forecasting capacity of the assays. The correlation of the P app value of the both assays with the literature reports showed good correlation of r 2 of 0.9487 and 0.930. The robustness of the established models was further evaluated by establishing correlation of in silico generated logBB values and the experimental logBB values (r 2 0.915). Thus, the developed models have the ability to identify the CNS penetration with reduced incubation times, which in turn will shorten the assay time especially when high throughput screening is employed.

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Strategies to assess blood–brain barrier penetration

Cited by 103 publications

References 46 publications

Species Independence in Brain Tissue Binding Using Brain Homogenates

Species Independence in Brain Tissue Binding Using Brain Homogenates

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

Optimization and Validation of an In Vitro Blood Brain Barrier Permeability Assay Using Artificial Lipid Membrane

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