Disobutamide: A model agent for investigating intracellular drug storage
Identifieur interne : 003135 ( Main/Exploration ); précédent : 003134; suivant : 003136Disobutamide: A model agent for investigating intracellular drug storage
Auteurs : Zadok Ruben [États-Unis] ; David C. Dodd [États-Unis] ; Kurt J. Rorig [États-Unis] ; Steven N. Anderson [États-Unis]Source :
- Toxicology and Applied Pharmacology [ 0041-008X ] ; 1989.
English descriptors
- Teeft :
- Acidic, Amine, Amphiphilic, Antiarrhythmic, Cationic, Cationic amphiphilic drugs, Cationic moiety, Cell monolayer, Cellular uptake, Choroid, Choroid plexus, Choroid plexus epithelium, Clear cytoplasmic vacuoles, Clear vacuoles, Concentric, Concentric lamellar bodies, Coronary arteries, Coronary artery, Coronary artery muscle cells, Culture medium, Cultured cells, Cytoplasmic, Cytoplasmic vacuoles, Disobutamide, Electron microscopy, Epithelial cells, Functional impairment, Golgi area, Histologic, Impairment, Intracellular, Intracellular drug storage, Intracellular storage, Lamellar, Liquid nitrogen, Moiety, Muscle cell, Muscle cells, Physiologic limits, Plexus, Prostate heart, Pyridine extraction, Rorig, Ruben, Same magnification, Stomach heart, Stomach kidney, Tapetal, Tertiary, Tertiary amine, Tertiary amines, Toxicity, Ultrastructural, Vacuolar, Vacuolation, Vacuole, Vesicle.
Abstract
Abstract: Disobutamide, a bis tertiary amine (pKa1 = 8.6; pKa2 = 10.2) cationic amphiphilic compound, and a putative cardiac antiarrhythmic drug induced clear cytoplasmic vacuoles in dogs and rats. Ultrastructurally, the vacuoles were membrane-bound vesicles containing primarily electron-lucent material. Some concentric lamellar bodies indicative of phospholipidosis were also present. Although numerous vacuoles were seen in one-year toxicity studies in dogs and rats, there was no apparent evidence of necrosis, inflammation, atrophy, hypoplasia, hyperplasia, or metaplasia. Clinical signs or laboratory findings indicative of functional impairment were also not apparent. The picture of the vacuolation in vivo was one of storage. In cultured cells vacuoles were shown to be storage sites for disobutamide and specifically in distended vesicles of the cytoplasmic acidic compartments, such as lysosomes, endocytic, and probably transport vesicles. Storage of the drug in acidic vesicles is compatible with the dibasic nature of the cationic moiety of disobutamide. The intrinsic cell chemicals which accumulate in the vacuoles along with disobutamide remain unknown. Disobutamide may be a useful agent for defining experimentally the borderline between physiologic limits (normal function) and toxicity (functional impairment) in the condition of intracellular drug storage abnormalities and for advancing knowledge of storage mechanisms.
Url:
DOI: 10.1016/0041-008X(89)90055-0
Affiliations:
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Le document en format XML
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<term>Cationic amphiphilic drugs</term>
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<term>Cellular uptake</term>
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<term>Intracellular drug storage</term>
<term>Intracellular storage</term>
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<term>Liquid nitrogen</term>
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<term>Ruben</term>
<term>Same magnification</term>
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<front><div type="abstract" xml:lang="en">Abstract: Disobutamide, a bis tertiary amine (pKa1 = 8.6; pKa2 = 10.2) cationic amphiphilic compound, and a putative cardiac antiarrhythmic drug induced clear cytoplasmic vacuoles in dogs and rats. Ultrastructurally, the vacuoles were membrane-bound vesicles containing primarily electron-lucent material. Some concentric lamellar bodies indicative of phospholipidosis were also present. Although numerous vacuoles were seen in one-year toxicity studies in dogs and rats, there was no apparent evidence of necrosis, inflammation, atrophy, hypoplasia, hyperplasia, or metaplasia. Clinical signs or laboratory findings indicative of functional impairment were also not apparent. The picture of the vacuolation in vivo was one of storage. In cultured cells vacuoles were shown to be storage sites for disobutamide and specifically in distended vesicles of the cytoplasmic acidic compartments, such as lysosomes, endocytic, and probably transport vesicles. Storage of the drug in acidic vesicles is compatible with the dibasic nature of the cationic moiety of disobutamide. The intrinsic cell chemicals which accumulate in the vacuoles along with disobutamide remain unknown. Disobutamide may be a useful agent for defining experimentally the borderline between physiologic limits (normal function) and toxicity (functional impairment) in the condition of intracellular drug storage abnormalities and for advancing knowledge of storage mechanisms.</div>
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