Amiodarone- and desethylamiodarone-induced pulmonary phospholipidosis, inhibition of phospholipases in vivo, and alteration of [14C]amiodarone uptake by perfused lung.
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.
Kodavanti
U P
UP
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
Mehendale
H M
HM
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000378:metabolism; D005856:Germ-Free Life; D008297:Male; D010741:Phospholipases A / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D012995:Solubility; D010738:Type C Phospholipases / Q000378:metabolism*
D010743:Phospholipids; D010741:Phospholipases A; D010738:Type C Phospholipases; C036116:desethylamiodarone; D000638:Amiodarone