Prediction of antiepileptic drug efficacy: the use of intracerebral microdialysis to monitor biophase concentrations

Clinckers, Ralph; Smolders, Ilse Julia; Vermoesen, Katia; Michotte, Yvette; Danhof, Meindert; Voskuyl, Rob A.; Pasqua, Oscar Della

doi:10.1517/17425250903146903

Cited by 13 publications

(2 citation statements)

References 88 publications

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“…In this case, a straightforward method to reliably estimate unbound drug concentrations in the brain is essential. Intracerebral microdialysis allows direct measurements of C u,b in preclinical species. , However, it should be acknowledged that this methodology is often characterized by high experimental complexity, low throughput, a propensity to generate artifacts, low recovery, and highly scattered data, especially for lipophilic compounds, thus limiting their application to support compound optimization in early drug discovery. These experimental limitations are important for compounds that are substrates of efflux transporters expressed at the BBB for which the free drug concentration hypothesis does not apply; therefore, C u,p cannot be used as a surrogate of C u,b .…”

Section: Introductionmentioning

confidence: 99%

Estimation of Drug Binding to Brain Tissue: Methodology and in Vivo Application of a Distribution Assay in Brain Polar Lipids

et al. 2015

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The unbound drug concentration-effect relationship in brain is a key aspect in CNS drug discovery and development. In this work, we describe an in vitro high-throughput distribution assay between an aqueous buffer and a microemulsion of porcine brain polar lipids (BPL). The derived distribution coefficient LogDBPL was applied to the prediction of unbound drug concentrations in brain (Cu,b) and nonspecific binding to brain tissue. The in vivo relevance of the new assay was assessed for a large set of proprietary drug candidates and CNS drugs by (1) comparing observed compound concentrations in rat CSF with Cu,b calculated using the LogDBPL assay in combination with total drug brain concentrations, (2) comparing Cu,b derived from LogDBPL and total drug brain concentrations to Cu,b estimated using in vitro P-glycoprotein efflux ratio data and unbound drug plasma levels, and (3) comparing tissue nonspecific binding data from human brain autoradiography studies for 17 PET tracer candidates to distribution in BPL. In summary, the LogDBPL assay provides a predicted drug fraction unbound in brain tissue that is nearly identical to brain homogenate equilibrium dialysis with an estimation of in vivo Cu,b that is superior to LogD in octanol. LogDBPL complements the approach for predicting Cu,b based on in vitro P-glycoprotein efflux ratio and in vivo unbound plasma concentration and stands as a fast and cost-effective tool for nonspecific brain binding optimization of PET ligand candidates.

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Section: Introductionmentioning

confidence: 99%

Estimation of Drug Binding to Brain Tissue: Methodology and in Vivo Application of a Distribution Assay in Brain Polar Lipids

et al. 2015

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“…Intracerebral microdialysis can provide important data to determine the blood–brain barrier transport characteristics and extracellular/biophase concentrations of a compound (Clinckers et al ., 2009). A prerequisite is that the intracerebral implantation of a microdialysis probe does not significantly alter the barrier's physiological and restrictive properties.…”

Section: Discussionmentioning

confidence: 99%

Using microdialysis to analyse the passage of monovalent nanobodies through the blood–brain barrier

Caljon

Caveliers

Lahoutte

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSE Nanobodies are promising antigen‐binding moieties for molecular imaging and therapeutic purposes because of their favourable pharmacological and pharmacokinetic properties. However, the capability of monovalent nanobodies to reach targets in the CNS remains to be demonstrated. EXPERIMENTAL APPROACH We have assessed the blood–brain barrier permeability of Nb_An33, a nanobody against the Trypanosoma brucei brucei variant‐specific surface glycoprotein (VSG). This analysis was performed in healthy rats and in rats that were in the encephalitic stage of African trypanosomiasis using intracerebral microdialysis, single photon emission computed tomography (SPECT) or a combination of both methodologies. This enabled the quantification of unlabelled and 99mTc‐labelled nanobodies using, respectively, a sensitive VSG‐based nanobody‐detection elisa, radioactivity measurement in collected microdialysates and SPECT image analysis. KEY RESULTS The combined read‐out methodologies showed that Nb_An33 was detected in the brain of healthy rats following i.v. injection, inflammation‐induced damage to the blood–brain barrier, as in the late encephalitic stage of trypanosomiasis, significantly increased the efficiency of passage of the nanobody through this barrier. Complementing SPECT analyses with intracerebral microdialysis improved analysis of brain disposition. There is clear value in assessing penetration of the blood–brain barrier by monovalent nanobodies in models of CNS inflammation. Our data also suggest that rapid clearance from blood might hamper efficient targeting of specific nanobodies to the CNS. CONCLUSIONS AND IMPLICATIONS Nanobodies can enter the brain parenchyma from the systemic circulation, especially in pathological conditions where the blood–brain barrier integrity is compromised.

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Introduction to the Microdialysis Technology

Müller

2012

Microdialysis in Drug Development

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Microdialysis (lD) has been established as a reliable in vivo tool to measure interstitial drug concentrations quasi online in virtually every given tissue and organ in animals and humans. Following its first description in the 1970s lD has been further developed and employed as a research and drug development tool in [14,000 PubMed publications. The rationale for the application of lD in Pharma R&D is based on the presence of blood to tissue barriers which hamper drug penetration to target sites. A clear understanding of target site pharmacokinetics (PK), as provided by lD and complementary techniques is a prerequisite for understanding drug action in vivo.

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Prediction of antiepileptic drug efficacy: the use of intracerebral microdialysis to monitor biophase concentrations

Cited by 13 publications

References 88 publications

Estimation of Drug Binding to Brain Tissue: Methodology and in Vivo Application of a Distribution Assay in Brain Polar Lipids

Estimation of Drug Binding to Brain Tissue: Methodology and in Vivo Application of a Distribution Assay in Brain Polar Lipids

Using microdialysis to analyse the passage of monovalent nanobodies through the blood–brain barrier

Introduction to the Microdialysis Technology

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