title: Comparative evaluation of amiodarone-induced phospholipidosis and drug accumulation in Fischer-344 and Sprague-Dawley rats.
abstract: Amiodarone (AD) and its major metabolite, desethylamiodarone (desethylAD), are both phospholipogenic. The present study was undertaken to evaluate the comparative susceptibilities of male Fischer-344 and Sprague-Dawley rats to AD-induced phospholipidosis in alveolar macrophages (AMs), liver and kidney tissue and the concomitant accumulation of AD and desethylAD in these cells, tissues and plasma. Rats were administered AD (100 mg/kg/day, p.o.) for 1 week. Plasma concentrations of AD and desethylAD were approximately 4- and 12-fold higher, respectively, in Fischer-344s compared to Sprague-Dawleys 24 h after the last dose. AD and desethylAD levels in AMs were approximately 12- and 25-fold higher, respectively, in Fischer-344s than Sprague-Dawleys. In the liver and kidney, levels of both compounds were also significantly higher in Fischer-344s than Sprague-Dawleys. Ultrastructural features indicative of phospholipidosis were not observed consistently in any tissue except AMs from treated Fischer-344s. AM total phospholipid increased nearly 5-fold in Fischer-344s, while Sprague-Dawleys showed no increase over control. AMs from both strains incubated with 10 microM AD or desethylAD in vitro were not significantly different in their accumulation of the compounds. When incubated with AD or desethylAD, the lysosomal phospholipases A1 partially purified from AMs of both strains were equally sensitive to inhibition as measured by the drug concentration giving 50% inhibition in activity (IC50). The results of this study indicate that at the same administered dose, AD and desethylAD, accumulate to higher tissue levels and are more phospholipogenic in male Fischer-344 rats than in male Sprague-Dawley rats. The basis for the high susceptibility of Fischer-344 rats to AM-induced phospholipidosis is unknown at present but appears not to be related to biochemical or cellular features of the AMs.
authors.affiliation: Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center of West Virginia University, Morgantown 26506-9223, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Reasor
authors.forename: C M
authors.initials: CM
authors.lastname: McCloud
authors.forename: T L
authors.initials: TL
authors.lastname: Beard
authors.forename: D C
authors.initials: DC
authors.lastname: Ebert
authors.forename: S
authors.initials: S
authors.lastname: Kacew
authors.forename: M F
authors.initials: MF
authors.lastname: Gardner
authors.forename: K A
authors.initials: KA
authors.lastname: Aldern
authors.forename: K Y
authors.initials: KY
authors.lastname: Hostetler
mesh_terms: D000638:Amiodarone / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D007668:Kidney / Q000378:metabolism; D008064:Lipidoses / Q000139:chemically induced*; D008099:Liver / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D010743:Phospholipids / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley
chemical_list: D000889:Anti-Arrhythmia Agents; D010743:Phospholipids; D010741:Phospholipases A; C036116:desethylamiodarone; D000638:Amiodarone