Amiodarone-induced phospholipidosis in rat alveolar macrophages.
Humans treated with the antiarrhythmic drug amiodarone may develop pulmonary toxicity accompanied by the presence of alveolar macrophages (AM) containing lamellar inclusions. This cellular response is indicative of the development of a drug-induced phospholipidosis. To characterize this response of the AM, Fischer-344 rats were treated with amiodarone, and the macrophages were recovered by pulmonary lavage. The development of phospholipidosis was dose- and time-dependent and was reversible. Daily treatment for 1 wk (5 days/wk) at 150 mg/kg resulted in a 5-fold increase in total phospholipid in the cells. Phospholipid levels were increased only slightly more through 9 wk of treatment. Cells were filled with lamellar inclusions and contained areas of amorphous granular and membranous material. Individual classes of phospholipids were all increased during the development of phospholipidosis. When expressed as mumol/10(7) cells, phosphatidylcholine demonstrated the largest increase. Levels of amiodarone and its major metabolite, desethylamiodarone, increased in AM in parallel with the increase in phospholipid. From 3 days through 9 wk of treatment, the level of desethylamiodarone was always higher than that of amiodarone. Treatment with desethylamiodarone also induced phospholipidosis in AM. Administration of phenobarbital along with amiodarone for 1 wk caused a reduction in the levels of amiodarone, desethylamiodarone, and phospholipid in the cells. The molar ratio of amiodarone to phospholipid was decreased, whereas the molar ratio of desethylamiodarone to phospholipid remained unchanged. Taken together, the results indicate that, along with amiodarone, desethylamiodarone and/or its metabolites may play an important role in the phospholipidosis induced in AM when rats are treated with amiodarone.
Reasor
M J
MJ
Department of Pharmacology and Toxicology, West Virginia University Medical Center, Morgantown 26506.
Ogle
C L
CL
Walker
E R
ER
Kacew
S
S
D000638:Amiodarone / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives; D000818:Animals; D004305:Dose-Response Relationship, Drug; D002479:Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D010743:Phospholipids / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains
D010743:Phospholipids; C036116:desethylamiodarone; D000638:Amiodarone