Preclinical Toxicity Studies of L-Buthionine Sulfoximine (BSO, NSC-326231) in Mice and Dogs

摘要

BSO was administered either intravenously (IV) or orally in a series of experiments conducted to determine (a) the effect of BSO on glutathione (GSH) in plasma (mice), whole blood (dogs), liver, lung, and kidney; (b) the bioavailabity of BSO; and (c) the toxicity of BSO following repeated administration to CD2F1 mice and beagle dogs. Data indicated that BSO was absorbed from the G.I. tract, but was rapidly removed and/or metabolized by the liver. At 800 mg/kg administered as a single IV or oral dose in mice, no clinical signs of toxicity were observed, but GSH was depleted in both plasma and tissue. Similar results were observed in mice following 100, 400, or 800 mg/kg/dose, three times per day for 5 days. Plasma GSH levels in dogs were low and erratic. Whole blood and tissue GSH levels were depleted by study day 4 following oral administration of 400 or 800 mg/kg/dose. BSO-related toxic signs were observed at these dose levels, however. Three of 4 dogs receiving 800 mg/kg/dose 3 times per day were sacrificed in a moribund condition following convulsions after 9 or 10 doses. Toxicity in the 400 mg/kg/dose for a total of 15 doses, dose groups appeared to be reversible.