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Physiologic Disposition and Intracellular Localization of Isometamidium¹

Pharmacology Section, Division of Experimental Chemotherapy, Sloan-Kettering Institute for Cancer Research, New York, New York

Isometamidium leaves the blood rapidly in rats after i.v. injection and within a few minutes most of the compound is found in liver and kidney. It remains for long periods in subcutaneous sites of injection from which it is transferred selectively to liver, kidney, and spleen. After s.c. injection none is detected in urine or bile and only small fractions of the compound appear daily in feces. Little is absorbed after intragastric administration and most of it is recovered in feces as unchanged drug and homidium. In dogs and monkeys large fractions of i.v. doses accumulate in liver and kidney cortex; significant amounts of unchanged drug are found in these sites for as long as 8 weeks after treatment. Hepatic and renal cumulation accounts for the quick recovery from the acute actions of the drug which are prominent after i.v. injection, for the greatly reduced toxicity of the agent when given i.p. or s.c., and for the pathologic changes seen in liver and kidney cortex. The agent also causes local tissue injury at injection sites and degranulation of mast cells.

Intracellular distribution in vivo can be studied by fluorescence microscopy. In rats bright fluorescence is seen in hepatocytes, tubules of the renal cortex, ducts of salivary glands, islets of the pancreas, and in granular clusters (macrophages?) in spleen, lymph nodes, and thymus. In hepatic cells and renal cortical tubules fluorescence is exclusively cytoplasmic and in hepatic cells mainly granular. The agent sediments with mitochondria of liver fractions from treated rats. Lysosomes may also contain high concentrations. Essentially none is found in the cell sap and only small amounts are associated with nuclei and microsomal particulates. Isometamidium is bound by serum albumin, deoxy- and ribonucleic acids, heparin, and hyaluronic acid. Insoluble complexes form with the nucleic acids and mucopolysaccharides when there is charge neutralization of the cationic drug and the polyanionic molecules. Binding does not explain localization of the agent in rat liver mitochondria in vivo although it accounts for staining of nuclei in vitro and for fluorochroming of mast cell granules.

¹ Aided by Cancer Chemotherapy National Service Center Contract SA-43-p4-2445 and Grants CA-03192 and CA-08748 from the National Cancer Institute, USPHS.

² Visiting Investigator, Chester Beatty Research Institute, London, September 1965 to July 1966, during tenure of an Alfred P. Sloan Award in Cancer Research.

Received 4/14/66. Accepted 9/12/66.

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