Carrier proteins determine local pharmacokinetics and arterial distribution of paclitaxel

Lovich, Mark A.; Creel, Chris; Hong, Kristy; Hwang, Chao Wei; Edelman, Elazer R.

doi:10.1002/jps.1085

Cited by 105 publications

(74 citation statements)

References 36 publications

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“…Drug properties (mainly hydrophobicity), arterial architecture and local pharmacology exert their own influence on drug release from devices and drug uptake at the stentartery interface (Hwang et al, 2003, Lovich et al, 2001). Thus, due to the high dependency of the drug release rate on many factors such as drug dose density, drug carrier, processing parameters or physiological transport forces, determination of elution kinetics is very necessary.…”

Section: Importance Of Controlled Drug Elution For Desmentioning

confidence: 99%

Mechanism of controlled release kinetics from medical devices

Raval

Parikh

2010

Braz. J. Chem. Eng.

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-Utilization of biodegradable polymers for controlled drug delivery has gained immense attention in the pharmaceutical and medical device industry to administer various drugs, proteins and other biomolecules both systematically and locally to cure several diseases. The efficacy and toxicity of this local therapeutics depends upon drug release kinetics, which will further decide drug deposition, distribution, and retention at the target site. Drug Eluting Stent (DES) presently possesses clinical importance as an alternative to Coronary Artery Bypass Grafting due to the ease of the procedure and comparable safety and efficacy. Many models have been developed to describe the drug delivery from polymeric carriers based on the different mechanisms which control the release phenomenon from DES. Advanced characterization techniques facilitate an understanding of the complexities behind design and related drug release behavior of drug eluting stents, which aids in the development of improved future drug eluting systems. This review discusses different drug release mechanisms, engineering principles, mathematical models and current trends that are proposed for drug-polymer coated medical devices such as cardiovascular stents and different analytical methods currently utilized to probe diverse characteristics of drug eluting devices.

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Section: Importance Of Controlled Drug Elution For Desmentioning

confidence: 99%

Mechanism of controlled release kinetics from medical devices

Raval

Parikh

2010

Braz. J. Chem. Eng.

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“…Microtubules have a similar cellular concentration of Ϸ10 Ϫ5 M (24). The nonuniform distribution of paclitaxel previously observed in the arterial wall may reflect an inhomogeneous distribution (13) of polymerized microtubules or carrier proteins (25). Although regulated at a coarse level by transport forces and lipid avidity, the distribution of paclitaxel and rapamycin is also regulated at a fine level by the distribution and availability of their protein targets, a level of control not present for drugs such as heparin that are rapidly cleared from arterial tissue.…”

mentioning

confidence: 92%

Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel

Levin

Vukmirovic

Hwang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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219

165

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Endovascular drug-eluting stents have changed the practice of medicine, and yet it is unclear how they so dramatically reduce restenosis and how to distinguish between the different formulations available. Biological drug potency is not the sole determinant of biological effect. Physicochemical drug properties also play important roles. Historically, two classes of therapeutic compounds emerged: hydrophobic drugs, which are retained within tissue and have dramatic effects, and hydrophilic drugs, which are rapidly cleared and ineffective. Researchers are now questioning whether individual properties of different drugs beyond lipid avidity can further distinguish arterial transport and distribution. In bovine internal carotid segments, tissue-loading profiles for hydrophobic paclitaxel and rapamycin are indistinguishable, reaching load steady state after 2 days. Hydrophilic dextran reaches equilibrium in several hours at levels no higher than surrounding solution concentrations. Both paclitaxel and rapamycin bind to the artery at 30 -40 times bulk concentration. Competitive binding assays confirm binding to specific tissue elements. Most importantly, transmural drug distribution profiles are markedly different for the two compounds, reflecting, perhaps, different modes of binding. Rapamycin, which binds specifically to FKBP12 binding protein, distributes evenly through the artery, whereas paclitaxel, which binds specifically to microtubules, remains primarily in the subintimal space. The data demonstrate that binding of rapamycin and paclitaxel to specific intracellular proteins plays an essential role in determining arterial transport and distribution and in distinguishing one compound from another. These results offer further insight into the mechanism of local drug delivery and the specific use of existing drug-eluting stent formulations.

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“…Membrane-surrounded micro-compartments with little convective stirring, such as synapses and other interstitial spaces, are now thought to represent an important extra 'diffusion boundary' for hydrophilic drugs [70,79] (Figure 3B). In intact tissues, targets at the cell plasma membrane are indeed most likely to face such liquid-filled cavities [80][81][82]. Moreover, the extracellular matrix as well as an unstirred layer of water molecules very close to the membrane constitute further obstacles that may hinder the approach and escape of drugs [83].…”

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confidence: 99%

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future. IntroductionThe pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2]. In accordance with this principle, the frequently observed time lag between the concentration of a drug in the systemic circulation and its effect was initially attributed to slow equilibration between the plasma and a hypothetical target-surrounding 'effect compartment' [3]. By contrast, preclinical screening studies traditionally aim to optimize drug candidates in terms of only their efficacy and potency (i.e. PD properties). Inherent to this practice is the proposal that drug-target interactions are adequately described by equilibrium equations and, hence, that association and dissociation rates play only subordinate roles. In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al. [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times. This property is now recognized to play a key role with respect to the clinical British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016...

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Carrier proteins determine local pharmacokinetics and arterial distribution of paclitaxel

Cited by 105 publications

References 36 publications

Mechanism of controlled release kinetics from medical devices

Mechanism of controlled release kinetics from medical devices

Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

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