Amantadine-induced lipidosis. A cytological and physicochemical study.
The purpose of this study was to test whether or not the antiviral drug amantadine induces the structural features of lipidosis in intact animals (rats) and cultured cells, and to investigate the interactions between amantadine and phospholipids. Chlorphentermine was used as reference compound. When subchronically fed to rats at a daily dosage of approximately 180 mg/kg, amantadine induced ultrastructural symptoms of generalized lipidosis, the degree of which was, however, by far less marked than that previously reported for chlorphentermine. This was paralleled by the findings on cell cultures (rat peritoneal macrophages), where the lipidosis-inducing potency of amantadine was approximately 10-fold lower than that of chlorphentermine. As to drug-phospholipid interactions, amantadine had less marked effects than chlorphentermine upon the phase transition characteristics of phosphatidylcholine and phosphatidic acid; furthermore, amantadine was approximately 10-fold less potent than chlorphentermine in displacing Ca from phosphatidylserine monolayers. The present study has revealed a parallel between the comparatively low lipidosis-inducing efficacy inherent to amantadine and the comparatively low tendency to interact with phospholipids. It is suggested that the cage-like structure of the amantadine molecule hinders an effective intercalation of the drug into phospholipid aggregates, and that this is an essential factor responsible for the low inherent efficacy of amantadine with respect to lipidosis induction.
D000547:Amantadine / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002745:Chlorphentermine / Q000633:toxicity; D002479:Inclusion Bodies / Q000187:drug effects; D007668:Kidney / Q000473:pathology; D008064:Lipidoses / Q000139:chemically induced* / Q000473:pathology; D008099:Liver / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology; D009420:Nervous System / Q000473:pathology; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013696:Temperature
D010743:Phospholipids; D000547:Amantadine; D002745:Chlorphentermine