Pentamidine accumulates in rat liver lysosomes and inhibits phospholipid degradation.
The subcellular distribution and the effects of pentamidine on the ultrastructure of the rat liver were studied. Rats were given single or repeated daily intraperitoneal injections of 10, 25 or 50 mg pentamidine isethionate/kg b. wt. for 1, 4, 6, 9 or 16 days. The livers were removed for ultrastructural and biochemical analyses on the day after termination of each series of injections and in addition 7 and 35 days after the 16th injection. Electron microscopy of liver tissues showed that the general cellular architecture of the hepatocytes was preserved. The subcellular organelles were normal, except for the secondary lysosomes, which were severely altered and laden with multilamellar, myelin structures (myelin bodies) that gradually increased with dose and time course following repeated injections. These altered lysosomes were enriched in phospholipids. The alteration of the lysosomes persisted for up to 5 weeks after cessation of administration. Pentamidine was highly enriched in the lysosomal fraction (30-50 times more than in the liver homogenate). It was calculated that the lysosomal pentamidine accounted 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 mechanism for organ toxicity.
Glaumann
H
H
Department of Infectious Diseases, Karolinska Institute, Sweden.
Bronner
U
U
Ericsson
O
O
Gustafsson
L L
LL
Rombo
L
L
D000818:Animals; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010419:Pentamidine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000378:metabolism
D010743:Phospholipids; D010419:Pentamidine