ChloroquineV1, Main, Exploration, bibRecord, 002E05

Cellular accumulation of amiodarone and desethylamiodarone in cultured human cells

Identifieur interne : 002E05 ( Main/Exploration ); précédent : 002E04; suivant : 002E06

Cellular accumulation of amiodarone and desethylamiodarone in cultured human cells

Auteurs : Ulrich E. Honegger [Suisse] ; Roger D. Zuehlke [Suisse] ; Isabel Scuntaro [Suisse] ; Markus H. A. Schaefer [Suisse] ; Hermann Toplak [Suisse] ; Ulrich N. Wiesmann [Suisse]

Source :

Biochemical Pharmacology [ 0006-2952 ] ; 1993.

RBID : ISTEX:E6A942C3F040556E03EAAE1610AE251C64FCD1C4

English descriptors

Abstract

Abstract: Amiodarone (AMIO), a potent antiarrhythmic drug, is clinically widely used despite its frequent side effects after chronic administration. These side effects coincide with an intralysosomal accumulation of AMIO and its main metabolite desethylamiodarone (DEA) and may be causally related to the drug-induced intracellular storage of phospholipids (PL). Kinetics of cellular uptake and release of radiolabelied AMIO and DEA were studied following single and multiple exposures of cultured human skin fibroblasts to 5 and 10 μM drug concentrations. AMIO and DEA were efficiently taken up into cultured cells. The rate of uptake was slower than that of other cationic amphiphilic drugs. The intracellular steady state concentrations were in the millimolar range suggesting a lysosomal trapping. Repetitive exposures of cultures resulted in a cumulative and partly saturable drug uptake. The accumulation of DEA was higher than that of AMIO throughout. AMIO and DEA previously taken up into the cells during a 2 hr exposure were completely released into the washing media, suggesting an exchangeable form of the accumulated drugs. Following repetitive exposures only part of the drugs was released. Under chasing conditions using washing media containing non-labelled AMIO and DEA respectively or ammonium chloride the release of the chronically accumulated 14C-labelled drugs was increased. This suggested a drug storage in the form of complexes in acidic compartments. Phospholipid (PL) content as well as individual PL fractions were changed in whole cells and in isolated plasma membranes. PL accumulation is assumed to occur by inhibition of PL degradation due to formation of non-degradable drug-PL complexes or by inhibition of phospholipase activities. Cellular PL accumulation seemed to interfere with PL recycling. Changes in PL composition of purified plasma membranes were in part complementary to the ones in whole cells. The alterations in membrane PL composition may explain the changes in membrane fluidity and the decrease in β-adrenoceptor density and in isoproterenol-stimulated cAMP formation. The results obtained provide an explanation for the pharmacokinetic, and possibly for the pharmacodynamic and also toxicological behaviour of AMIO and DEA in vivo.

Url:

https://api.istex.fr/ark:/67375/6H6-BS02HCR5-M/fulltext.pdf

DOI: 10.1016/0006-2952(93)90070-D

Affiliations:

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Le document en format XML

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<series><title level="j">Biochemical Pharmacology</title>
<title level="j" type="abbrev">BCP</title>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-[4-(trimethyl-amino-phenyl]-6-phenylhexa-1,3,5-triene</term>
<term>3-isobutyl-1-methylxanthin</term>
<term>AMIO</term>
<term>BSA</term>
<term>CAD</term>
<term>CGP 12177</term>
<term>DEA</term>
<term>HPTLC</term>
<term>IBMX</term>
<term>IL-1</term>
<term>MEM</term>
<term>PA</term>
<term>PBS</term>
<term>PC</term>
<term>PE</term>
<term>PI</term>
<term>PL</term>
<term>PMV</term>
<term>PS</term>
<term>SPH</term>
<term>TMA-DPH</term>
<term>[4-(3-tert. butylamino-2-hydroxypropoxy)-benzimidazole-2-on hydrochloride]</term>
<term>amiodarone</term>
<term>bovine serum albumin</term>
<term>cationic amphiphilic drug</term>
<term>desethylamiodarone</term>
<term>high pressure thin layer chromatography</term>
<term>interleukin 1</term>
<term>minimal essential medium</term>
<term>phosphate-buffered saline</term>
<term>phosphatidic acid</term>
<term>phosphatidylcholine</term>
<term>phosphatidylethanolamin</term>
<term>phosphatidylinositol</term>
<term>phosphatidylserin</term>
<term>phospholipids</term>
<term>plasma membrane vesicles</term>
<term>sphingomyelin</term>
</keywords>
<keywords scheme="Teeft" xml:lang="en"><term>Adverse effects</term>
<term>Amio</term>
<term>Amiodarone</term>
<term>Ammonium chloride</term>
<term>Anisotropy</term>
<term>Biochem</term>
<term>Biochem pharmacol</term>
<term>Bovine serum albumin</term>
<term>Camp formation</term>
<term>Cell cultures</term>
<term>Cell protein</term>
<term>Cellular</term>
<term>Cellular contents</term>
<term>Cellular drug uptake</term>
<term>Cellular protein</term>
<term>Cellular uptake</term>
<term>Chronic administration</term>
<term>Chronic drug exposures</term>
<term>Cold solution</term>
<term>Concentration gradient</term>
<term>Confluent</term>
<term>Confluent monolayer cultures</term>
<term>Control cells</term>
<term>Control cultures</term>
<term>Cultured</term>
<term>Cultured cells</term>
<term>Cumulative uptake</term>
<term>Daily doses</term>
<term>Desethylamiodarone</term>
<term>Dos</term>
<term>Drug concentrations</term>
<term>Drug release</term>
<term>Drug storage</term>
<term>Drugexposed cells</term>
<term>Exchangeable form</term>
<term>Extracellular</term>
<term>Extracellular drug concentrations</term>
<term>Fibroblast</term>
<term>Fluidity</term>
<term>Fluorescence anisotropy</term>
<term>Glass coverslips</term>
<term>Honegger</term>
<term>Identical conditions</term>
<term>Individual experiments</term>
<term>Initial concentration</term>
<term>Intracellular</term>
<term>Intracellular concentrations</term>
<term>Intracellular drug</term>
<term>Lipid</term>
<term>Lipid composition</term>
<term>Lysosomal</term>
<term>Lysosomal storage</term>
<term>Macrophage</term>
<term>Main metabolite desethylamiodarone</term>
<term>Membrane</term>
<term>Membrane fluidity</term>
<term>Monolayer</term>
<term>Monolayer cultures</term>
<term>Multiple exposures</term>
<term>Open columns</term>
<term>Other cads</term>
<term>Other cationic amphiphilic drugs</term>
<term>Phosphatidic acid</term>
<term>Phospholipid</term>
<term>Plasma membrane</term>
<term>Plasma membrane vesicles</term>
<term>Plasma membranes</term>
<term>Radiolabelled</term>
<term>Radiolabelled drug</term>
<term>Receptor density</term>
<term>Repetitive</term>
<term>Repetitive doses</term>
<term>Repetitive exposures</term>
<term>Saturable drug uptake</term>
<term>Side effects</term>
<term>Significant reduction</term>
<term>Single dose</term>
<term>Single exposures</term>
<term>Skin fibroblasts</term>
<term>Slower rate</term>
<term>Storage site</term>
<term>Thyroid gland</term>
<term>Uptake</term>
<term>Uptake period</term>
<term>Whole cells</term>
</keywords>
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<front><div type="abstract" xml:lang="en">Abstract: Amiodarone (AMIO), a potent antiarrhythmic drug, is clinically widely used despite its frequent side effects after chronic administration. These side effects coincide with an intralysosomal accumulation of AMIO and its main metabolite desethylamiodarone (DEA) and may be causally related to the drug-induced intracellular storage of phospholipids (PL). Kinetics of cellular uptake and release of radiolabelied AMIO and DEA were studied following single and multiple exposures of cultured human skin fibroblasts to 5 and 10 μM drug concentrations. AMIO and DEA were efficiently taken up into cultured cells. The rate of uptake was slower than that of other cationic amphiphilic drugs. The intracellular steady state concentrations were in the millimolar range suggesting a lysosomal trapping. Repetitive exposures of cultures resulted in a cumulative and partly saturable drug uptake. The accumulation of DEA was higher than that of AMIO throughout. AMIO and DEA previously taken up into the cells during a 2 hr exposure were completely released into the washing media, suggesting an exchangeable form of the accumulated drugs. Following repetitive exposures only part of the drugs was released. Under chasing conditions using washing media containing non-labelled AMIO and DEA respectively or ammonium chloride the release of the chronically accumulated 14C-labelled drugs was increased. This suggested a drug storage in the form of complexes in acidic compartments. Phospholipid (PL) content as well as individual PL fractions were changed in whole cells and in isolated plasma membranes. PL accumulation is assumed to occur by inhibition of PL degradation due to formation of non-degradable drug-PL complexes or by inhibition of phospholipase activities. Cellular PL accumulation seemed to interfere with PL recycling. Changes in PL composition of purified plasma membranes were in part complementary to the ones in whole cells. The alterations in membrane PL composition may explain the changes in membrane fluidity and the decrease in β-adrenoceptor density and in isoproterenol-stimulated cAMP formation. The results obtained provide an explanation for the pharmacokinetic, and possibly for the pharmacodynamic and also toxicological behaviour of AMIO and DEA in vivo.</div>
</front>
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<name sortKey="Honegger, Ulrich E" sort="Honegger, Ulrich E" uniqKey="Honegger U" first="Ulrich E." last="Honegger">Ulrich E. Honegger</name>
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Cellular accumulation of amiodarone and desethylamiodarone in cultured human cells

Cellular accumulation of amiodarone and desethylamiodarone in cultured human cells

Source :

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri