Biomaterial Database

Amiodarone- and desethylamiodarone-induced pulmonary phospholipidosis, inhibition of phospholipases in vivo, and alteration of [14C]amiodarone uptake by perfused lung. 1991

U P Kodavanti, and H M Mehendale

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.

Amiodarone (AM) pulmonary phospholipidosis in patients receiving this drug is well recognized. We investigated the in vivo phospholipidosis-inducing potency of AM and its major nonpolar metabolite, desethylamiodarone (DEA), in rats, their ability to inhibit phospholipases, and also the effects on pulmonary uptake of [14C] AM. Fisher-344 male rats (200 to 250 g) were given AM or DEA (100 mg/kg/d orally) for 2, 7, or 21 d. Food consumption and body weight gain were significantly reduced by both AM and DEA treatment. The control rats, therefore, were pair-fed. Both drugs increased the number of cells in lavage during the treatment. Lung/body weight ratio increased after 21 d of treatment in AM rats. Mortality increased to 100% by day 10 in DEA-treated rats, unlike in AM-treated rats, where 20 to 30% of the animals died during this period and thereafter. No further mortality occurred during 21 d of treatment. Levels of phospholipids increased in lavaged lung, alveolar lavage cells, and surfactant material in AM- as well as DEA-treated rats. However, there was no significant difference between the two treatment groups. Phospholipases A and C were measured in lysosomal soluble fractions of lavaged lung and sonicated lung lavage cells. Both drugs exerted inhibitory action on phospholipases in the lavage cells but, to some extent, spared phospholipases in lysosomal plus mitochondrial soluble fraction isolated from lavaged lung with reversibility in enzyme inhibition despite continuous treatment. [14C] AM uptake by perfused lung, lavage cells as well as surfactant supernatant was increased in AM- and DEA-treated rats. Again, increase in pulmonary uptake of [14C]AM was similar in AM- and DEA-treated rats. These results thus suggest: (1) DEA is more toxic to rats than is AM, at the dose level used. The ability to sequester AM and the parameters related to phospholipidosis revealed no significant differences between these two analogs. (2) Both drugs are inhibitors of lavage cell phospholipases and also are inhibitory to lung lysosomal phospholipases to a lesser extent. Recovery of lung phospholipases occurred despite continuous treatment. (3) AM- and DEA-induced phospholipidosis increased the uptake of [14C]AM by perfused lung. (4) The mechanism of AM-induced pulmonary phospholipidosis includes selective in vivo inhibition of phospholipases.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D010738	Type C Phospholipases	A subclass of phospholipases that hydrolyze the phosphoester bond found in the third position of GLYCEROPHOSPHOLIPIDS. Although the singular term phospholipase C specifically refers to an enzyme that catalyzes the hydrolysis of PHOSPHATIDYLCHOLINE (EC 3.1.4.3), it is commonly used in the literature to refer to broad variety of enzymes that specifically catalyze the hydrolysis of PHOSPHATIDYLINOSITOLS.	Lecithinase C,Phospholipase C,Phospholipases, Type C,Phospholipases C
D010741	Phospholipases A	Phospholipases that hydrolyze one of the acyl groups of phosphoglycerides or glycerophosphatidates.
D010743	Phospholipids	Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides see GLYCEROPHOSPHOLIPIDS) or sphingosine (SPHINGOLIPIDS). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system.	Phosphatides,Phospholipid
D011650	Pulmonary Alveoli	Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place.	Alveoli, Pulmonary,Alveolus, Pulmonary,Pulmonary Alveolus
D011916	Rats, Inbred F344	An inbred strain of rat that is used for general BIOMEDICAL RESEARCH purposes.	Fischer Rats,Rats, Inbred CDF,Rats, Inbred Fischer 344,Rats, F344,Rats, Inbred Fisher 344,CDF Rat, Inbred,CDF Rats, Inbred,F344 Rat,F344 Rat, Inbred,F344 Rats,F344 Rats, Inbred,Inbred CDF Rat,Inbred CDF Rats,Inbred F344 Rat,Inbred F344 Rats,Rat, F344,Rat, Inbred CDF,Rat, Inbred F344,Rats, Fischer
D001992	Bronchoalveolar Lavage Fluid	Washing liquid obtained from irrigation of the lung, including the BRONCHI and the PULMONARY ALVEOLI. It is generally used to assess biochemical, inflammatory, or infection status of the lung.	Alveolar Lavage Fluid,Bronchial Lavage Fluid,Lung Lavage Fluid,Bronchial Alveolar Lavage Fluid,Lavage Fluid, Bronchial,Lavage Fluid, Lung,Pulmonary Lavage Fluid,Alveolar Lavage Fluids,Bronchial Lavage Fluids,Bronchoalveolar Lavage Fluids,Lavage Fluid, Alveolar,Lavage Fluid, Bronchoalveolar,Lavage Fluid, Pulmonary,Lavage Fluids, Alveolar,Lavage Fluids, Bronchial,Lavage Fluids, Bronchoalveolar,Lavage Fluids, Lung,Lavage Fluids, Pulmonary,Lung Lavage Fluids,Pulmonary Lavage Fluids
D005856	Germ-Free Life	Animals not contaminated by or associated with any foreign organisms.	Axenic Animals,Gnotobiotics,Germfree Life,Animal, Axenic,Animals, Axenic,Axenic Animal,Germ Free Life,Gnotobiotic,Life, Germ-Free,Life, Germfree
D000638	Amiodarone	An antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting POTASSIUM CHANNELS and VOLTAGE-GATED SODIUM CHANNELS. There is a resulting decrease in heart rate and in vascular resistance.	Amiobeta,Amiodarex,Amiodarona,Amiodarone Hydrochloride,Amiohexal,Aratac,Braxan,Corbionax,Cordarex,Cordarone,Kordaron,L-3428,Ortacrone,Rytmarone,SKF 33134-A,Tachydaron,Trangorex,Hydrochloride, Amiodarone,L 3428,L3428,SKF 33134 A,SKF 33134A
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia