PHARMACOLOGIC DISPOSITION OF 4'-(9-ACRIDINYLAMINO)METHANESULFON-META-ANISIDIDE IN MICE AND RATS

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  • 1 January 1977
    • journal article
    • research article
    • Vol. 5  (6) , 579-590
Abstract
The pharmacologic disposition of 4''-(9-acridinylamino)methanesulfon-m-anisidide (AMSA; NSC-141549), a new antitumor agent presently under consideration for phase 1 evaluation in man, was studied in mice and rats with 14C-AMSA labeled in the 9-C of the acridine ring. Radioactivity was selectively localized in the liver where it was present as metabolites of AMSA. After 2 h, nearly 50% of the plasma radioactivity was bound to protein and did not dissociate on Sephadex G-200 chromatography. Radioactivity was rapidly eliminated in the bile; > 50% of the administered dose was excreted by this route in 2 h. Bile/plasma ratios of > 400:1 indicated an active transport mechanism. The biliary transport mechanism was saturable with therapeutic doses. AMSA was espectially vulnerable to nucleophilic attack by alkylthiols resulting in displacement of 4-amino-3-methoxymethanesulfonanilide and the formation of the corresponding 9-alkyl-thioether of acridine. The major radioactive biliary metabolite (accounting for 90-95% of the biliary radioactivity) possessed the same chromatographic properties as the thiolysis product of AMSA and glutathione (GSH). A 40% reduction in liver GSH and a 20% reduction of liver GSH-transferase activity occurred after AMSA administration to mice. The pharmacologic disposition of AMSA can best be explained by a nonenzymatic nucleophilic attack on the 9-C atom of AMSA by endogenous thiols, resulting in the formation of 9-thioethers of acridine. Such an attack by low molecular weight thiols results in a product that is eliminated in urine and bile, whereas interaction with protein-thiol groups results in prolonged retention of the acridine moiety.

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