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Bree, J. B. M. M. Van; Tio, Susan; Boer, Albertus G. de; Verhoef, J.; Breimer, D. D.

doi:10.1023/a:1015838532048

Cited by 16 publications

(3 citation statements)

References 29 publications

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“…Several in vitro, in vivo, and in situ techniques for quantifying the passage of substances have been described. [64] The usual indicator for passage is the brain uptake index (BUI). This compares the ratio of the concentration of test substance taken up by the brain and the amount injected luminally with the ratio of the concentration of a reference substance (e.g.…”

Section: Transport Processes Within the Blood-brain Barriermentioning

confidence: 99%

Transport and Detoxication: Principles, Approaches, and Perspectives for Research on the Blood – Brain Barrier

Aigner

Wolf

Gassen

1997

Angew. Chem. Int. Ed. Engl.

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The blood–brain barrier is an anatomical constraint that maintains homeostasis within the brain and consists of uniquely structured brain capillaries. In addition to these morphological features, a number of specific proteins and transport systems (which are relevant to pharmaceutical applications) can be described that complement barrier functions and ensure a selective supply of substances from the blood to the brain. The additional role of the blood–brain barrier as a site of active detoxication by metabolizing and thus defending against neurotoxic substances has only become apparent in the past few years. Fundamental to understanding these processes are the principles of detoxication reactions and metabolic pathways of excretory organs, which will be described briefly here. The confirmation of these mechanisms in the brain enhances understanding of the complex protective functions of the blood–brain barrier. Evidently, these detoxication pathways simultaneously produce metabolites with neurotoxic or, in case of leukotriene, blood–brain barrier damaging potential. Finally, a detailed description of the mercapturic acid pathway of detoxication will be used to illustrate how evidence of representative enzymes can be used to distinguish definite functions of particular cell types and marker proteins of the blood–brain barrier.

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Section: Transport Processes Within the Blood-brain Barriermentioning

confidence: 99%

Transport and Detoxication: Principles, Approaches, and Perspectives for Research on the Blood – Brain Barrier

Aigner

Wolf

Gassen

1997

Angew. Chem. Int. Ed. Engl.

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“…The first study showing the feasibility of time course studies in CSF focused on heptabarbital [ 48 ]. Next the technique was applied to study the CNS distribution of desglycinamide-arginine vaspressin (DGAVP) as prototype peptide [ 49 ]. By applying the “unit impulse response” technology, analyzing the concentration profiles following intravenous and intracerebral administration, the input profile in the CNS could be determined [ 50 ].…”

Section: The Impact On Pharmacodynamics Research: Towards Physiology mentioning

confidence: 99%

Kinetics of drug action in disease states: towards physiology-based pharmacodynamic (PBPD) models

Danhof

2015

J Pharmacokinet Pharmacodyn

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Gerhard Levy started his investigations on the “Kinetics of Drug Action in Disease States” in the fall of 1980. The objective of his research was to study inter-individual variation in pharmacodynamics. To this end, theoretical concepts and experimental approaches were introduced, which enabled assessment of the changes in pharmacodynamics per se, while excluding or accounting for the cofounding effects of concomitant changes in pharmacokinetics. These concepts were applied in several studies. The results, which were published in 45 papers in the years 1984–1994, showed considerable variation in pharmacodynamics. These initial studies on kinetics of drug action in disease states triggered further experimental research on the relations between pharmacokinetics and pharmacodynamics. Together with the concepts in Levy’s earlier publications “Kinetics of Pharmacologic Effects” (Clin Pharmacol Ther 7(3): 362–372, 1966) and “Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin” (Clin Pharmacol Ther 10(1): 22–35, 1969), they form a significant impulse to the development of physiology-based pharmacodynamic (PBPD) modeling as novel discipline in the pharmaceutical sciences. This paper reviews Levy’s research on the “Kinetics of Drug Action in Disease States”. Next it addresses the significance of his research for the evolution of PBPD modeling as a scientific discipline. PBPD models contain specific expressions to characterize in a strictly quantitative manner processes on the causal path between exposure (in terms of concentration at the target site) and the drug effect (in terms of the change in biological function). Pertinent processes on the causal path are: (1) target site distribution, (2) target binding and activation and (3) transduction and homeostatic feedback.

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“…In order to describe the tightness status of the BBB in vivo or in vitro, next to transendothelial electrical resistance (TEER), determining the permeability of sucrose, Evans blue and FITC labeled dextrans (FD) became the methods of choice. At least since the late 1980s it has been known that commercially available FDs contain various amounts of free FITC [5] and consist of a wide range of polymers with different molecular weights. Commonly, total fluorescence values have been measured in permeation studies without considering the size of the different fluorescent fractions.…”

Section: Introductionmentioning

confidence: 99%