Tissue drug accumulation and ultrastructural changes during amiodarone administration in rats

Kannan, R.; Sarma, J. S. M.; Guha, Martin; Venkataraman, Kalyanasundaram

doi:10.1016/0272-0590(89)90334-5

Cited by 30 publications

(10 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Drug-induced phospholipidosis has been defined as an excessive, reversible accumulation of phospholipid and associated drug in lysosomes and as actually being predictive of drug and/or metabolite accumulation (Chatman et al, 2009). Phospholipidotic drugs accumulate in tissues, may show continued accumulation with no evidence of a plateau, are eliminated from these depots very slowly, and after cessation of drug treatment can be detected in the tissue even though they are undetectable in the blood (Camus and Mehendale, 1986;Kannan et al, 1989;Pellegatti and Pagliarusco, 2011). Phospholipidosis induced by one drug can result in an enhanced accumulation of a second, co-administered, drug (Ohmiya et al, 1983;Reasor, 1991), with potential for the development of additive changes.…”

Section: Considerations For Adversity and Risk Assessmentmentioning

confidence: 99%

Foamy macrophage responses in the rat lung following exposure to inhaled pharmaceuticals: a simple, pragmatic approach for inhaled drug development

Lewis

Williams

Beck

2013

J of Applied Toxicology

View full text Add to dashboard Cite

Successes in the field of respiratory medicines are largely limited to three main target classes: β2 -adrenergic receptor agonists, muscarinic antagonists and corticosteroids. A significant factor in attrition during the development of respiratory medicines is the induction of foamy macrophage responses, particularly, in rats. The term foamy macrophage describes a vacuolated cytoplasmic appearance, seen by light microscopy, which is ultrastructurally characterized by the presence of lysosomal lamellar bodies, neutral lipid droplets or drug particles. We propose a simple classification, based light-heartedly on the theme 'the good, the bad and the ugly', which allows important distinctions to be made between phenotypes, aetiologies and adversity. Foamy macrophages induced in rat lungs by exposure to inhaled β2 -agonists, antimuscarinics and corticosteroids are simple aggregates of uniform cells without other associated pathologies. In contrast, macrophage reactions induced by some other inhaled drug classes are more complex, associated with neutrophilic or lymphocytic infiltrations with/without damage to the adjacent alveolar walls. Foamy macrophage responses induced by inhaled drugs may be ascribed to either phagocytosis of poorly soluble drug particles, or to pharmacology. Both corticosteroids and β2 -agonists increase surfactant synthesis whereas muscarinic antagonists may decrease surfactant breakdown, due to inhibition of phospholipase C, both of which lead to phagocytosis of excess surfactant. Simple foamy macrophage responses are considered non-adverse, whereas ones that are more complex are designated as adverse. The development of foamy macrophage responses has led to confusion in interpretation and we hope this review helps clarify what is in fact a relatively simple, predictable, easily interpretable, commonly induced change.

show abstract

Section: Considerations For Adversity and Risk Assessmentmentioning

confidence: 99%

Foamy macrophage responses in the rat lung following exposure to inhaled pharmaceuticals: a simple, pragmatic approach for inhaled drug development

Lewis

Williams

Beck

2013

J of Applied Toxicology

View full text Add to dashboard Cite

show abstract

“…It also has antiarrhythmic activity, significantly increasing the action potential duration (class III antiarrhythmic effect) and decreasing the maximum rate of depolarization (class I antiarrhythmic effect) at clinically relevant concentrations [ 10 , 11 ]. After amiodarone treatment, amiodarone and DEA rapidly and extensively accumulate in extracardiac tissues (notably in the liver, lung and adipose tissue), even achieving μmol/g concentrations [ 12 – 14 ] and has a very long elimination half-life [ 13 , 15 , 16 ]. Tissue concentrations of amiodarone and DEA are 100 times higher than the corresponding plasma concentrations [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…After amiodarone treatment, amiodarone and DEA rapidly and extensively accumulate in extracardiac tissues (notably in the liver, lung and adipose tissue), even achieving μmol/g concentrations [ 12 – 14 ] and has a very long elimination half-life [ 13 , 15 , 16 ]. Tissue concentrations of amiodarone and DEA are 100 times higher than the corresponding plasma concentrations [ 15 , 16 ]. Extensive tissue accumulation of DEA and its long elimination time can give a possible role to DEA in progressive, muscle-invasive bladder cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Desethylamiodarone—A metabolite of amiodarone—Induces apoptosis on T24 human bladder cancer cells via multiple pathways

et al. 2017

View full text Add to dashboard Cite

Bladder cancer (BC) is a common malignancy of the urinary tract that has a higher frequency in men than in women. Cytostatic resistance and metastasis formation are significant risk factors in BC therapy; therefore, there is great interest in overcoming drug resistance and in initiating research for novel chemotherapeutic approaches. Here, we suggest that desethylamiodarone (DEA)–a metabolite of amiodarone—may have cytostatic potential. DEA activates the collapse of mitochondrial membrane potential (detected by JC-1 fluorescence), and induces cell death in T24 human transitional-cell bladder carcinoma cell line at physiologically achievable concentrations. DEA induces cell cycle arrest in the G0/G1 phase, which may contribute to the inhibition of cell proliferation, and shifts the Bax/Bcl-2 ratio to initiate apoptosis, induce AIF nuclear translocation, and activate PARP-1 cleavage and caspase-3 activation. The major cytoprotective kinases—ERK and Akt—are inhibited by DEA, which may contribute to its cell death-inducing effects. DEA also inhibits the expression of B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) and reduces colony formation of T24 bladder carcinoma cells, indicating its possible inhibitory effect on metastatic potential. These data show that DEA is a novel anti-cancer candidate of multiple cell death-inducing effects and metastatic potential. Our findings recommend further evaluation of its effects in clinical studies.

show abstract

“…Whereas the plasma concentrations were generally dose-proportional (see Table 1), the mean brain concentrations of AZD3783 were 38- and 460-fold higher at 14 and 47 mg/kg/day dose, respectively, relative to that at 2.3 mg/kg/day. Since CADs, e.g., amidarone, have been shown to accumulate in tissues in association with PLD 35 , one may hypothesize that the high brain to plasma concentration ratio is due to PLD, following accumulation of AZD3783 in lysosomes. On the other hand, at each dose, the concentrations of AZD3783 in the different brain regions were similar, i.e., there was no measureable preferential distribution of AZD3783 in select regions of the brain where dose-dependent PLD-like vacuolation was observed (e.g.…”

Section: Discussionmentioning

confidence: 99%

Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT<sub>1B</sub> Inhibitor

et al. 2014

View full text Add to dashboard Cite

AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine (5-HT1B) receptor, was explored as a potential treatment for depression. To support clinical trials, repeat dose toxicity studies in rats and dogs were conducted. Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month study, there were minimal neuronal vacuolation in the brain, a marked increase in liver enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD), and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86 days. Extensive pathologic changes were seen in all animals in retina epithelium (inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung, kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues. Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and pathology study showed that the concentration of AZD3783 in the brain was approximately 4 times higher than in the plasma after 4 weeks of dosing, however, they were similar in all regions examined, and did not correlate with areas with pathologic findings. Our findings with AZD3783 in dogs have not been reported previously with other CNS compounds that effect through serotonergic pharmacology.

show abstract

Tissue drug accumulation and ultrastructural changes during amiodarone administration in rats

Cited by 30 publications

References 27 publications

Foamy macrophage responses in the rat lung following exposure to inhaled pharmaceuticals: a simple, pragmatic approach for inhaled drug development

Foamy macrophage responses in the rat lung following exposure to inhaled pharmaceuticals: a simple, pragmatic approach for inhaled drug development

Desethylamiodarone—A metabolite of amiodarone—Induces apoptosis on T24 human bladder cancer cells via multiple pathways

Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT<sub>1B</sub> Inhibitor

Contact Info

Product

Resources

About