COMPARATIVE-EVALUATION OF AMIODARONE-INDUCED PHOSPHOLIPIDOSIS AND DRUG ACCUMULATION IN FISCHER-344 AND SPRAGUE-DAWLEY RATS

Amiodarone (AD) and its major metabolite, desethylamiodarone (desethyl AD), are both phospholipogenic. The present study was undertaken to ev aluate the comparative susceptibilities of male Fischer-344 and Spragu e-Dawley rats to AD-induced phospholipidosis in alveolar macrophages ( AMs), liver and kidney tissue and the concomitant accumulation of AD a nd desethylAD in these cells, tissues and plasma. Rats were administer ed 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 highe r, respectively, in Fischer-344s than Sprague-Dawleys. In the liver an d kidney, levels of both compounds were also significantly higher in F ischer-344s than Sprague-Dawleys. Ultrastructural features indicative of phospholipidosis were not observed consistently in any tissue excep t AMs from treated Fischer-344s, AM total phospholipid increased nearl y 5-fold in Fischer-344s, while Sprague-Dawleys showed no increase ove r control. AMs from both strains incubated with 10 mu M AD or desethyl AD in vitro were not significantly different in their accumulation of the compounds. When incubated with AD or desethylAD, the lysosomal pho spholipases A(1) partially purified from AMs of both strains were equa lly sensitive to inhibition as measured by the drug concentration givi ng 50% inhibition in activity (IC50). The results of this study indica te that at the same administered dose, AD and desethylAD, accumulate t o higher tissue levels and are more phospholipogenic in male Fischer-3 44 rats than in male Sprague-Dawley rats. The basis for the high susce ptibility of Fischer-344 rats to AM-induced phospholipidosis is unknow n at present but appears not to be related to biochemical or cellular features of the AMs.