Binding of Drugs in Serum, Blood Cells and Tissues of Rabbits with Experimental Acute Renal Failure

Peer, Avivit; Belpaire, F. M.; Bogaert, Marc G.

doi:10.1159/000137483

Cited by 11 publications

(4 citation statements)

References 7 publications

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“…Brain slices have been used to assess brain tissue binding in the literature (Van Peer et al, 1981), where 1000-m brain slices were incubated for 1 h. The rate of diffusion and time to achieve equilibrium was a concern for that study. To address these issues, the effect of brain slice thickness and the duration of incubation were assessed.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Utility of Brain Slice Methods to Study Brain Penetration

Becker

Liu²

2006

Drug Metab Dispos

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ABSTRACT:The objective of this study was to evaluate the utility of brain tissue slices to determine the effect of plasma and brain tissue nonspecific binding on the brain-to-plasma ratio (K p ). Mouse or rat brain slices (400 m) were prepared using a McIlwain tissue chopper (Surrey, UK) and incubated with 1 g/ml of compound at 37°C either in a physiological buffer to determine the buffer-to-slice concentration ratio, i.e., unbound fraction in brain tissue (f u,slice ), or in plasma to determine the slice-to-plasma concentration ratio (C slice /C plasma ). The unbound fraction in plasma, f u,plasma , was determined using equilibrium dialysis. In vitro-in vivo correlation of the brain-to-plasma ratio was examined for 13 and eight model compounds in mice and rats, respectively. C slice /C plasma and f u,plasma /f u,slice predicted the K p in rats, and C slice /C plasma predicted the K p in FVB mice for non-P-glycoprotein substrates within 3-fold but overpredicted K p for P-glycoprotein substrates by more than 3-fold. However, C slice /C plasma predicted the K p in mdr1a/1b knockout mice for both non-P-glycoprotein and P-glycoprotein substrates. Our present study demonstrates that a brain slice method can be used to differentiate whether a compound having a low K p is due to the effect of low nonspecific binding to brain tissue relative to plasma proteins or because of efflux transport at the blood-brain barrier.Brain is separated from the systemic circulation by two barriers: a blood-brain barrier (BBB) and a blood-cerebrospinal-fluid barrier (BCSFB). The BBB and BCSFB represent physical and enzymatic barriers that restrict and regulate the penetration of compounds into and out of the brain and maintain the homeostasis of the brain microenvironment (Davson and Segal, 1995). Brain penetration is essential for compounds where the site of action is within the central nervous system (CNS). For targets outside the CNS, BBB penetration may need to be minimized to reduce CNS-related side effects (Chen et al., 2003).The brain-to-plasma concentration ratio (K p ) is the most commonly used parameter for measuring brain penetration in a drug discovery setting. A large K p is considered a favorable property of a good CNS compound. This approach implies that a compound having a high K p penetrates into brain tissue better than one having a low K p . However, according to the definition of K p (K p ϭ C brain /C plasma ) and unbound fraction in plasma (f u,plasma ϭ C u,plasma /C plasma ) and brain (f u,brain ϭ C u,brain /C brain ), the following equation can be obtained:K p,in , defined as the ratio of f u,plasma over f u,brain , can be considered the "intrinsic" partition coefficient between brain and plasma. It is determined by nonspecific binding in brain and plasma and is not related to BBB properties. K p,free , defined as the ratio of the free brain concentration (C u,brain ) over the free plasma concentration (C u,plasma ), delineates BBB properties and governs the relationship between free brain and plasma concentrations...

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Section: Discussionmentioning

confidence: 99%

Evaluation of the Utility of Brain Slice Methods to Study Brain Penetration

Becker

Liu²

2006

Drug Metab Dispos

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“…The first use of this method for evaluation of intracerebral distribution of substances aimed to estimate the uptake of nutrients such as glucose and amino acids into the brain (McIlwain 1951a;Blasberg et al 1970;Newman et al 1988a;Newman et al 1991;Smith 1991). Later, the method was proposed for in vitro investigation of the distribution of drugs in the brain (Van Peer et al 1981;Kakee et al 1996Kakee et al , 1997Ooie et al 1997). There have been several efforts to establish mechanistic pharmacokinetic/pharmacodynamics links using brain slice methodology, e.g., for propofol (Gredell et al 2004), etomidate (Benkwitz et al 2007), and volatile agents (Chesney et al 2003).…”

Section: Fig 101mentioning

confidence: 99%

“…Moreover, researchers have used slices from different planes of the brain, such as hypothalamic (Kakee et al 1997), cortical (Kodaira et al 2011), or striatal (Friden et al 2009a(Friden et al , 2009b. The thickness of the brain slices also differs between protocols: 300 μm (Kakee et al 1996(Kakee et al , 1997Friden et al 2009a, b), 400 μm , or even 1000 μm (Van Peer et al 1981). Accordingly, the incubation time (time required to reach equilibrium) varies and could be 8 h or longer, which may be too long to sustain the viability of the slices.…”

Section: Preparation Of Brain Slices and Incubationmentioning

confidence: 99%

Drug Discovery Methods for Studying Brain Drug Delivery and Distribution

Loryan

Hammarlund‐Udenaes

2013

Drug Delivery to the Brain

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Methods used in drug discovery laboratories for assessing the delivery of small molecules to the brain have changed significantly in recent years. There is now more focus on measuring or estimating target unbound drug concentrations in the brain and evaluating the quantitative aspects of drug transport across the bloodbrain barrier (BBB). The techniques for investigation of the rate and extent of BBB transport of new chemical entities (NCEs) are discussed in this chapter. Combinatory methodology for rapid mapping of the extent of brain drug delivery via assessment of the unbound drug brain partitioning coefficient is presented. The chapter also explains the procedures for approximation of subcellular distribution of NCEs, particularly into the lysosomes. The principles, technical issues, advantages, and potential applications of techniques for evaluation of intra-brain distribution, i.e., equilibrium dialysis-based brain homogenate and brain slice methods, are described. The assessment of extent of BBB transport and intracellular distribution of NCEs, the identification of intra-brain distribution patterns, and their integration with pharmacodynamic measurements are valuable implements for candidate evaluation and selection in drug discovery and development. Abbreviations A brainAmount of drug in brain tissue AUC tot,brain Area under the total brain concentration-time curve AUC tot,plasma Area under the total plasma concentration-time curve BBB Blood-brain barrier

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“…Currently, this method is accepted as a standard approach in the pharmaceutical industry. However, the methodological limitations inherent to homogenizing the tissue provided impetus for developing the organotypic brain slice assay for investigation of both drug binding and cellular uptake into the brain tissue (24,66,67). Development of a brain slice assay suitable for the evaluation of the unbound volume of drug distribution in the brain, V u,brain, for test compounds in a drug discovery setting, which was validated against data generated by in vivo brain microdialysis, represented a significant advancement in the field (68,69).…”

Section: Introductionmentioning

confidence: 99%

Unbound Brain-to-Plasma Partition Coefficient, Kp,uu,brain—a Game Changing Parameter for CNS Drug Discovery and Development

et al. 2022

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Purpose More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (Kp,uu,brain) by Prof. Margareta Hammarlund-Udenaes, which was enabled by advancements in experimental methodologies including cerebral microdialysis. Since then, growing knowledge and data continue to support the notion that the unbound (free) concentration of a drug at the site of action, such as the brain, is the driving force for pharmacological responses. Towards this end, Kp,uu,brain is the key parameter to obtain unbound brain concentrations from unbound plasma concentrations. Methods To understand the importance and impact of the Kp,uu,brain concept in contemporary drug discovery and development, a survey has been conducted amongst major pharmaceutical companies based in Europe and the USA. Here, we present the results from this survey which consisted of 47 questions addressing: 1) Background information of the companies, 2) Implementation, 3) Application areas, 4) Methodology, 5) Impact and 6) Future perspectives. Results and conclusions From the responses, it is clear that the majority of the companies (93%) has established a common understanding across disciplines of the concept and utility of Kp,uu,brain as compared to other parameters related to brain exposure. Adoption of the Kp,uu,brain concept has been mainly driven by individual scientists advocating its application in the various companies rather than by a top-down approach. Remarkably, 79% of all responders describe the portfolio impact of Kp,uu,brain implementation in their companies as ‘game-changing’. Although most companies (74%) consider the current toolbox for Kp,uu,brain assessment and its validation satisfactory for drug discovery and early development, areas of improvement and future research to better understand human brain pharmacokinetics/pharmacodynamics translation have been identified.

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Binding of Drugs in Serum, Blood Cells and Tissues of Rabbits with Experimental Acute Renal Failure

Cited by 11 publications

References 7 publications

Evaluation of the Utility of Brain Slice Methods to Study Brain Penetration

Evaluation of the Utility of Brain Slice Methods to Study Brain Penetration

Drug Discovery Methods for Studying Brain Drug Delivery and Distribution

Unbound Brain-to-Plasma Partition Coefficient, Kp,uu,brain—a Game Changing Parameter for CNS Drug Discovery and Development

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