PENTAMIDINE ACCUMULATES IN RAT-LIVER LYSOSOMES AND INHIBITS PHOSPHOLIPID DEGRADATION

The subcellular distribution and the effects of pentamidine on the ult rastructure of the rat liver were studied. Rats were given single or r epealed daily intraperitoneal injections of 10, 25 or 50 mg pentamidin e isethionate/kg b. wt. for 1, 4, 6, 9 or 16 days. The livers were rem oved for ultrastructural and biochemical analyses on the day after ter mination of each series of injections and in addition 7 and 35 days af ter the 16th injection. Electron microscopy of liver tissues showed th at the general cellular architecture of the hepatocytes was preserved. The subcellular organelles were normal, except for the secondary lyso somes, which were severely altered and laden with multilamellar, myeli n structures (myelin bodies) that gradually increased with dose and ti me course following repeated injections. These altered lysosomes were enriched in phospholipids. The alteration of the lysosomes persisted f or up to 5 weeks after cessation of administration. Pentamidine was hi ghly enriched in the lysosomal fraction (30-50 times more than in the liver homogenate). It was calculated that the lysosomal pentamidine ac counted for practically all pentamidine distributed to the liver. The demonstrated accumulation of pentamidine in the lysosomes may explain the known large volume of distribution of this drug and may be one mec hanism for organ toxicity.