THE ACCUMULATION OF PENTAMIDINE AND THE TOXIC EFFECTS OF THE DRUG, ITS SELECTED ANALOGS AND METABOLITES ON ISOLATED ALVEOLAR CELLS

Radiolabelled [H-3]pentamidine is accumulated into 48-h and 7-day cult ures of alveolar epithelial type 2 cells and alveolar macrophages in a linear, time and dose-dependent manner, with the rate of uptake being 15.3, 13.4 and 17.9 pmol/mug protein per 30 min, respectively. Uptake was not affected by metabolic inhibitors. The differential toxicity o f the parent drug pentamidine, rive analogues and six metabolites was assessed on freshly isolated and type 2 cells maintained in culture ov er 24 h. Toxicity, determined by the attachment ability of alkaline ph osphatase positive cells containing lamellar bodies was greater in fre shly isolated cells. Overall, three/four of the analogues proved less damaging to type 2 cells than the pentamidine with one derivative [1,3 -bis(4-amidino-2-methoxy)propane], a compound particularly efficacious against pneumocystis in rats, showing minimal toxicity. Five metaboli tes (chain hydroxylated derivatives) were less toxic than the parent d rug. However, one metabolite (NN-dihydroxy derivative) was much more t oxic than pentamidine to both type 2 cells and alveolar macrophages. I t is concluded that as the type 2 cell can accumulate the drug, it rep resents a target cell which is particularly sensitive to pentamidine a nd/or some of its metabolites.