{'fraction_non_alphanumeric': 0.032117583015786606, 'fraction_numerical': 0.021230266739248774, 'mean_word_length': 5.2517006802721085, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
The pharmacologic disposition of 4'-(9-acridinylamino)methanesulfon-m-anisidide in mice and rats.

The pharmacologic disposition of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA; NSC-141549), a new antitumor agent presently under consideration for phase I evaluation in man, was studied in mice and rats with 14C-AMSA labeled in the 9-carbon of the acridine ring. Radioactivity was selectively localized in the liver where it was present mainly as metabolites of AMSA. After 2 hr, nearly 50% of the plasma radioactivity was bound to protein and did not dissociate upon Sephadex G-200 chromatography. Radioactivity was rapidly eliminated in the bile; greater than 50% of the administered dose was excreted by this route in 2 hr. Bile/plasma ratios of greater than 400:1 indicated an active transport mechanism. The biliary transport mechanism was saturable with therapeutic doses. AMSA was found to be especially vulnerable to nucleophilic attack by alkylthiols resulting in displacement of 4-amino-3-methoxymethanesulfonanilide and the formation of the corresponding 9-alkylthioether 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-carbon 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.