Brain Uptake of L‐Tryptophan and Diazepam: The Role of Plasma Protein Binding

Fenerty, Catherine A.; Lindup, W E

doi:10.1111/j.1471-4159.1989.tb07350.x

Cited by 17 publications

(15 citation statements)

References 34 publications

(33 reference statements)

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“…Second, other investigators argue that the protein-bound fraction contributes a significant portion of the total amount delivered to cells. 64 In other words, there might be some sort of facilitation process going on that enhances the extracellular protein-bound drug to interact with cell surface and dissociate from the albumin-binding site to deliver more unbound drug to cells (i.e., extracellular protein-facilitated uptake mechanism). Hence, the current literature suggests the existence of a so-called albumin-mediated uptake process.…”

Section: Tissue Concentration In Physiologically Based Pharmacokinetimentioning

confidence: 99%

The Role of Extracellular Binding Proteins in the Cellular Uptake of Drugs: Impact on Quantitative In Vitro -to- In Vivo Extrapolations of Toxicity and Efficacy in Physiologically Based Pharmacokinetic-Pharmacodynamic Research

Poulin

Burczynski

Haddad

2016

Journal of Pharmaceutical Sciences

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A critical component in the development of physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) models for estimating target organ dosimetry in pharmacology and toxicology studies is the understanding of the uptake kinetics and accumulation of drugs and chemicals at the cellular level. Therefore, predicting free drug concentrations in intracellular fluid will contribute to our understanding of concentrations at the site of action in cells in PBPK/PD research. Some investigators believe that uptake of drugs in cells is solely driven by the unbound fraction; conversely, others argue that the protein-bound fraction contributes a significant portion of the total amount delivered to cells. Accordingly, the current literature suggests the existence of a so-called albumin-mediated uptake mechanism(s) for the protein-bound fraction (i.e., extracellular protein-facilitated uptake mechanisms) at least in hepatocytes and cardiac myocytes; however, such mechanism(s) and cells from other organs deserve further exploration. Therefore, the main objective of this present study was to discuss further the implication of potential protein-facilitated uptake mechanism(s) on drug distribution in cells under in vivo conditions. The interplay between the protein-facilitated uptake mechanism(s) and the effects of a pH gradient, metabolism, transport, and permeation limitation potentially occurring in cells was also discussed, as this should violate the basic assumption on similar free drug concentration in cells and plasma. This was made because the published equations used to calculate drug concentrations in cells in a PBPK/PD model did not consider potential protein-facilitated uptake mechanism(s). Consequently, we corrected some published equations for calculating the free drug concentrations in cells compared with plasma in PBPK/PD modeling studies, and we proposed a refined strategy for potentially performing more accurate quantitative in vitro-to-in vivo extrapolations (IVIVEs) of toxicity (efficacy) at the cellular level from data generated in cell assays. Overall, this present study may help to optimize the human dose prediction in preclinical and clinical studies, while prescribing drugs with narrow therapeutic windows that are highly bound to extracellular proteins and/or highly ionized at the physiological pH. This may facilitate building a more accurate safety (efficacy) profile for such drugs.

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Section: Tissue Concentration In Physiologically Based Pharmacokinetimentioning

confidence: 99%

The Role of Extracellular Binding Proteins in the Cellular Uptake of Drugs: Impact on Quantitative In Vitro -to- In Vivo Extrapolations of Toxicity and Efficacy in Physiologically Based Pharmacokinetic-Pharmacodynamic Research

Poulin

Burczynski

Haddad

2016

Journal of Pharmaceutical Sciences

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“…18,19 However, there are some cases in which the free form of a drug does not directly correlate with its tissue uptake or bioavailability. 16,17,20–28 This has led to some competing models to describe drug delivery and uptake, such as those that incorporate receptor-mediated transport of drugs that are bound to specific serum proteins 23, 25 or those in which the rate of a drug/protein interaction falls in a range that can contribute to deviations from the free drug hypothesis. 16, 17, 24, 27 Rate constant measurements for these interactions are needed to compare these models, to determine when the free drug fraction is important, and to better predict the in vivo behavior that would be expected for a drug.…”

Section: Introductionmentioning

confidence: 99%

Measurement of Drug−Protein Dissociation Rates by High-Performance Affinity Chromatography and Peak Profiling

2009

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The rate at which a drug or other small solute interacts with a protein is important in understanding the biological and pharmacokinetic behavior of these agents. One approach that has been developed for examining these rates involves the use of high-performance affinity chromatography (HPAC) and estimates of band-broadening through peak profiling. Previous work with this method has been based on a comparison of the statistical moments for a retained analyte versus non-retained species at a single, high flow rate to obtain information on stationary phase mass transfer. In this study an alternative approach was created that allows a broad range of flow rates to be used for examining solute-protein dissociation rates. Chromatographic theory was employed to derive equations that could be used with this approach on a single column, as well as with multiple columns to evaluate and correct for the impact of stagnant mobile phase mass transfer. The interaction of L-tryptophan with human serum albumin was used as a model system to test this method. A dissociation rate constant of 2.7 (± 0.2) s−1 was obtained by this approach at pH 7.4 and 37°C, which was in good agreement with previous values determined by other methods. The techniques described in this report can be applied to other biomolecular systems and should be valuable for the determination of drug-protein dissociation rates.

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“…The binding affinity of albumin has been reported to vary with albumin concentration for numerous other metabolites and drugs, including cortisol (8,11), sulfobromophthalein (12), thiopental (13), phenytoin (14), tryptophan (14,15), sulfadiazine (9), salicylate (9), phenylbutazone (9), and a benzoic acid derivative (16). The mechanism of this effect is unknown, but may reflect formation of reversible aggregates of albumin at higher concentrations.…”

Section: Table I Estimates Of Impurity Levels and Formation Rates Usimentioning

confidence: 99%

“…Moreover, many properties of albumin are known to depend on its concentration (7)(8)(9)(10). In particular, the binding affinity of albumin for a variety of metabolites and drugs is reduced at higher albumin concentra-tion (8,9,(11)(12)(13)(14)(15)(16). Thus, the assumption that the K F for bilirubin is unaffected by albumin concentration may not be valid.…”

mentioning

confidence: 96%

Affinity of Human Serum Albumin for Bilirubin Varies with Albumin Concentration and Buffer Composition

Weisiger¹,

Ostrow²,

Koehler³

et al. 2001

Journal of Biological Chemistry

106

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Albumin binding is a crucial determinant of bilirubin clearance in health and bilirubin toxicity in certain disease states. However, prior attempts to measure the affinity of albumin for bilirubin have yielded highly variable results, reflecting both differing conditions and the confounding influence of impurities. We therefore have devised a method based on serial ultrafiltration that successively removes impurities in [ 14 C]bilirubin until a stable binding affinity is achieved, and then we used it to assess the effect of albumin concentration and buffer composition on binding. The apparent binding affinity of human serum albumin for [ 14 C]bilirubin was strongly dependent on assay conditions, falling from (5.09 ؎ 0.24) ؋ 10 7 liters/mol at lower albumin concentrations (15 M) to (0.54 ؎ 0.05) ؋ 10 7 liters/mol at higher albumin concentrations (300 M). To determine whether radioactive impurities were responsible for this change, we estimated impurities in the stock bilirubin using a novel modeling approach and found them to be 0.11-0.13%. Formation of new impurities during the study and their affinity for albumin were also estimated. After correction for impurities, the binding affinity remained heavily dependent on the albumin concentration (range (5.37 ؎ 0.26) ؋ 10 7 liters/mol to (0.65 ؎ 0.03) ؋ 10 7 liters/ mol). Affinities decreased by about half in the presence of chloride (50 mM). Thus, the affinity of human albumin for bilirubin is not constant, but varies with both albumin concentration and buffer composition. Binding may be considerably less avid at physiological albumin concentrations than previously believed.

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Brain Uptake of L‐Tryptophan and Diazepam: The Role of Plasma Protein Binding

Cited by 17 publications

References 34 publications

The Role of Extracellular Binding Proteins in the Cellular Uptake of Drugs: Impact on Quantitative In Vitro -to- In Vivo Extrapolations of Toxicity and Efficacy in Physiologically Based Pharmacokinetic-Pharmacodynamic Research

The Role of Extracellular Binding Proteins in the Cellular Uptake of Drugs: Impact on Quantitative In Vitro -to- In Vivo Extrapolations of Toxicity and Efficacy in Physiologically Based Pharmacokinetic-Pharmacodynamic Research

Measurement of Drug−Protein Dissociation Rates by High-Performance Affinity Chromatography and Peak Profiling

Affinity of Human Serum Albumin for Bilirubin Varies with Albumin Concentration and Buffer Composition

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