Assessment of Blood–Brain Barrier Permeability Using the In Situ Mouse Brain Perfusion Technique

Zhao, Rongsheng; Kalvass, J. Cory; Pollack, Gary M.

doi:10.1007/s11095-009-9876-4

Cited by 39 publications

(31 citation statements)

References 37 publications

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“…Examples of CL in (K in ) values from in situ brain perfusion and microdialysis studies are given in Table 5.1. It can be clearly seen, when Mdr1a(+/+) and (Zhao et al 2009) Mdra1a(−/−) mice are compared, that CL in is decreased in the presence of P-gp. CL in therefore describes the net influx clearance across the BBB.…”

Section: Methods and Relationshipsmentioning

confidence: 97%

Pharmacokinetic Concepts in Brain Drug Delivery

Hammarlund‐Udenaes

2013

Drug Delivery to the Brain

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This chapter presents the pharmacokinetic principles of blood-brain barrier (BBB) transport and the intra-brain distribution of drugs in order to provide a basis for understanding drug delivery to the brain from a clinically relevant perspective. The most important concentrations to measure when determining drug distribution are those of the unbound drug, because it is the unbound drug that causes the pharmacological effect by interacting with the target. Therefore, this chapter also discusses the pharmacokinetic basis, the kind of information provided, and the in vivo relevance of the methods used to obtain reliable, therapeutically useful estimates of brain drug delivery. The main factors governing drug distribution to the brain are the permeability of the BBB to the drug (influx clearance), the extent of nonspecific binding to brain tissue, and the efflux clearance of the drug. The ratio of the influx and efflux clearances provides an estimation of the extent of drug equilibration across the BBB, described by K p,uu,brain . This parameter is important, as active uptake and/or efflux transporters influence the absolute brain concentrations of unbound drug in relation to those in plasma. The advantage of using K p,uu,brain during the drug discovery process lies in its ability to predict the potential success of drugs intended for action within the brain or, conversely, of those with few or no side effects in the brain.

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Section: Methods and Relationshipsmentioning

confidence: 97%

Pharmacokinetic Concepts in Brain Drug Delivery

Hammarlund‐Udenaes

2013

Drug Delivery to the Brain

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“…The synthe- 37 sized compounds were subjected to basic cytotoxic and antimicrobial tests. The synthetic protocol is 38 described separately for each of the three series of the target amides, because each series of compounds 39 required a different synthetic approach.…”

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confidence: 99%

“…528 Lipinski [35] and Ghose [36] The blood brain barrier (BBB) and plasma protein binding are 533 two of the important factors affecting distribution of the com-534 pound in the human body. Several parameters assist in evaluation 535 of each potential drug for its BBB transport [37]. 536 The rules describe molecular properties important for a small 537 molecule drug pharmacokinetics in the human body, including 538 their absorption, distribution, metabolism and excretion (ADME 539 parameters) [35,36].…”

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confidence: 99%

Polyamine derivatives of betulinic acid and β-sitosterol: A comparative investigation

et al. 2015

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“…Being unidirectional, the PS describes the speed at which the drug enters the brain (Fenstermacher 1992;Tanaka and Mizojiri 1999;Gaillard and de Boer 2000;Summerfield et al 2007;Liu et al 2008;Zhao et al 2009). Generally, fast permeation is a key requirement for drugs when rapid CNS onset is wanted, e.g., for general anesthetics, and analgesics.…”

Section: Introductionmentioning

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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Assessment of Blood–Brain Barrier Permeability Using the In Situ Mouse Brain Perfusion Technique

Cited by 39 publications

References 37 publications

Pharmacokinetic Concepts in Brain Drug Delivery

Pharmacokinetic Concepts in Brain Drug Delivery

Polyamine derivatives of betulinic acid and β-sitosterol: A comparative investigation

Drug Discovery Methods for Studying Brain Drug Delivery and Distribution

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