Time‐Dependent Effects of Hydrophobic Amine‐Containing Drugs on Lysosome Structure and Biogenesis in Cultured Human Fibroblasts

Logan, Randall; Kong, Alex C.; Krise, Jeffrey P.

doi:10.1002/jps.24087

Cited by 24 publications

(27 citation statements)

References 46 publications

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“…Nevertheless, understanding the mechanisms responsible for the accumulation of drugs within intracellular compartments is important as it may explain why some drugs fail to reach proper therapeutic concentrations at a site of action or to explain unfavorable drug-drug interactions that may occur through bioaccumulation dependent pathways [35]. Drug trapping and accumulation can lead to alterations in the structure and function of organelles, affecting cell physiology [36]. Accumulation of small molecule drugs in organs such as the liver and kidney are particularly concerning as a potential cause of toxicity [37,38].…”

Section: Discussionmentioning

confidence: 99%

Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy

Rzeczycki

Yoon

Keswani

et al. 2017

Biomed. Opt. Express

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Abstract:Following prolonged administration, certain orally bioavailable but poorly soluble small molecule drugs are prone to precipitate out and form crystal-like drug inclusions (CLDIs) within the cells of living organisms. In this research, we present a quantitative multiparameter imaging platform for measuring the fluorescence and polarization diattenuation signals of cells harboring intracellular CLDIs. To validate the imaging system, the FDAapproved drug clofazimine (CFZ) was used as a model compound. Our results demonstrated that a quantitative multi-parameter microscopy image analysis platform can be used to study drug sequestering macrophages, and to detect the formation of ordered molecular aggregates formed by poorly soluble small molecule drugs in animals.

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Section: Discussionmentioning

confidence: 99%

Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy

Rzeczycki

Yoon

Keswani

et al. 2017

Biomed. Opt. Express

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“…It is also possible that the concentration of propranolol in vivo is sufficiently low to provide some beneficial effect on uptake. In light of the fact that amine-containing drugs such as propranolol can accumulate inside lysosomes in a time-dependent fashion 30 , sustained treatment with beta-blockers, even at low initial doses, could ultimately exhibit negative effects. Regardless, the fact that the increased rhGAA uptake does not result in increased glycogen clearance in muscle points to a secondary consequence of β-blocker treatment.…”

Section: Discussionmentioning

confidence: 99%

A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease

Han

Pope

et al. 2016

Molecular Genetics and Metabolism

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Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) fails to completely reverse muscle weakness in Pompe disease. β2-agonists enhanced ERT by increasing receptor-mediated uptake of rhGAA in skeletal muscles. Purpose To test the hypothesis that a β-blocker might reduce the efficacy of ERT, because the action of β-blockers opposes those of β2-agonists. Methods Mice with Pompe disease were treated with propranolol (a β-blocker) or clenbuterol in combination with ERT, or with ERT alone. Results Propranolol-treated mice had decreased weight gain (p<0.01), in comparison with clenbuterol-treated mice. Left ventricular mass was decreased (and comparable to wild-type) in ERT only and clenbuterol-treated groups of mice, and unchanged in propranolol-treated mice. GAA activity increased following either clenbuterol or propranolol in skeletal muscles. However, muscle glycogen was reduced only in clenbuterol-treated mice, not in propranolol-treated mice. Cell-based experiments confirmed that propranolol reduces uptake of rhGAA into Pompe fibroblasts and also demonstrated that the drug induces intracellular accumulation of glycoproteins at higher doses. Conclusion Propranolol, a commonly prescribed β-blocker, increased left ventricular mass and decreased glycogen clearance in skeletal muscle following ERT. β-blockers might therefore decrease the efficacy from ERT in patients with Pompe disease.

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“…Based on their physicochemical properties, [20][21][22][23] these substrates are defined as cationic amphiphilic drugs, and they are expected to be subjected to lysosomal trapping. The study in lysosome-rich tissues has suggested the significant influence of lysosomal trapping on drug distribution, [26][27][28][29] and this has raised the possibility that lysosomal trapping affects the blood-to-retina transport of cationic drugs. However, little is known about lysosomal trapping in the retinal capillary endothelial cells (inner BRB), and the present study investigated lysosomal trapping in retinal capillary endothelial cells using LTR as a fluorescent probe for lysosomal trapping.…”

Section: Discussionmentioning

confidence: 99%

“…carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; FCCP) that reduces the pH-gradient between the cytosol and lysosomes. [22][23][24][25] The importance of lysosomal trapping in the distribution of cationic drugs has been suggested in lysosome-rich tissues such as liver and lung, [26][27][28][29] implying a possibility that lysosomal trapping resides in retinal capillary endothelial cells to exert influence on the blood-to-retina transport of neuroprotective cations.…”

mentioning

confidence: 99%

Lysosomal Trapping Is Present in Retinal Capillary Endothelial Cells: Insight into Its Influence on Cationic Drug Transport at the Inner Blood–Retinal Barrier

Kubo

Seko

Usui

et al. 2016

Biological & Pharmaceutical Bulletin

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Lysosomal trapping was investigated in the retinal capillary endothelial cells that are responsible for the inner blood-retinal barrier (BRB) using LysoTracker ® Red (LTR). Using confocal microscopy on TR-iBRB2 cells, an in vitro model of the inner BRB, the presence of lysosomal trapping in retinal capillary endothelial cells was suggested since TR-iBRB2 cells exhibited punctuate intracellular localization of LTR that was attenuated by NH 4 Cl treatment. The study confirmed that LTR uptake by retinal capillary endothelial cells took place in a time-and temperature-dependent manner, and exhibited the 1.58-fold greater uptake at pH 8.4 than that at pH 7.4 while there was no change in uptake between pH 6.4 and pH 7.4, suggesting that passive diffusion is not enough to explain LTR uptake. The inhibition study showed the possible influence of lysosomal trapping on cationic drug transport by retinal capillary endothelial cells since LTR uptake was significantly inhibited by cationic amphiphilic drugs. Inhibition profiling and the estimation of IC 50 suggested the influence of lysosomal trapping on propranolol and low-affinity pyrilamine transport while lysosomal trapping had only a partial effect on verapamil, clonidine, nicotine and high-affinity pyrilamine transport in retinal capillary endothelial cells.

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Time‐Dependent Effects of Hydrophobic Amine‐Containing Drugs on Lysosome Structure and Biogenesis in Cultured Human Fibroblasts

Cited by 24 publications

References 46 publications

Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy

Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy

A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease

Lysosomal Trapping Is Present in Retinal Capillary Endothelial Cells: Insight into Its Influence on Cationic Drug Transport at the Inner Blood–Retinal Barrier

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