CHRONIC TOXICITY, METABOLISM, AND PHARMACOKINETICS OF THE 5-HT3 RECEPTOR ANTAGONIST ZATOSETRON (LY277359) IN FISCHER-344 RATS

Studies were done to characterize the chronic toxicity, metabolism, an d pharmacokinetics of a 5-HT3 receptor antagonist in Fischer 344 rats. Animals were given daily gavage doses of 10, 30, or 90 (females only were increased from 90 to 120 mg/kg for months 7-12) mg/kg of zatosetr on for 1 year. Treatment-related histologic changes occurred primarily in the liver and kidney of rats given 30 or 90/120 mg/kg and consiste d of hepatocellular fatty change (males only), hepatic granuloma forma tion, and histiocytosis (females only), and renal pigment deposition ( both sexes), lesions not previously described in animals treated with 5-HT, receptor antagonists. Decreased erythrocyte parameters, increase d total leukocyte, lymphocyte, and neutrophil counts, and increased se rum alkaline phosphatase, gamma glutamyltransferase, alanine transamin ase, and liver weights in females were most likely related to the chro nic inflammatory process in the liver. Increased alanine transaminase and transiently increased alkaline phosphatase with increased liver we ights in males were likely related to the hepatocellular fatty change. Increased renal tubular epithelial pigment deposition (lipofuscin and hemosiderin) was observed in males and females in the high-dose group and in females in the middle-dose group. Both had increased kidney we ights and increased serum inorganic phosphorus. Females in the high-do se group had increased urine volume, decreased pH, and increased total excretion of sodium, potassium, chloride, and creatinine. These chang es may have been a reflection of tubular dysfunction associated with e xcessive pigment deposition. No toxicologically significant effects oc curred in rats treated with 10 mg/kg/day for 1 year. Plasma concentrat ions of zatosetron and its 3-hydroxy metabolite increased with increas ing dose and duration of dosing in both males and females during the f irst 6 months of dosing. Subsequent values measured at 12 months showe d no substantive increases except in males given the highest dose. At comparable doses, consistent sex differences (F > M) in mean 1-hr plas ma content of parent compound were evident across dose and time. Zatos etron-induced hepato- and nephrotoxicity seems to be peculiar to the r at and is observed only at very high doses relative to the proposed hu man clinical dose. (C) 1994 Society of Toxicology.