TOXICITY OF THE PROTEIN-KINASE-C INHIBITOR SAFINGOL ADMINISTERED ALONE AND IN COMBINATION WITH CHEMOTHERAPEUTIC-AGENTS

Safingol [(2S,3S)-2-amino-1,3-octadecanediol] potentiates the toxicity of doxorubicin (DOX) and cisplatin (CIS) against tumor cells in vitro and in vivo. The present studies were conducted in rats and dogs to e valuate safingol toxicity when administered iv as a single agent and t o evaluate safingol's ability to potentiate the toxicity of establishe d chemotherapeutic agents to normal tissues in vivo. In an escalating dose study, dogs were administered safingol iv at 5, 10, 20, 30, 40, a nd 75 mg/kg on Days 1 through 6. Necropsies were performed on Day 7. R ed urine was observed at 10 mg/kg and higher. Icterus was observed fol lowing 40 mg/kg with additional signs of hypoactivity and anorexia occ urring after 75 mg/kg. Clinical and microscopic pathology revealed mar ked hepatotoxicity, venous degeneration and necrosis at injection site s, and evidence of intravascular hemolysis. Doses of 5, 20, or 40 mg s afingol/kg were utilized in single iv dose rat and dog studies. No evi dence of adverse systemic toxicity was seen up to 20 mg/kg in either s pecies [for rats: C-max = 12,600 (males) or 17,133 (females) ng/ml, AU C = 3853 (males) or 4365 (females) ng X hr/ml; for dogs: C-max = 2533 ng/ml, AUC = 2851 ng X hr/ml (no sex differences)]. Local effects of v enous irritation or intravascular hemolysis were observed at all doses in rats and at 20 and 40 mg/kg in dogs. A dose of 40 mg/kg [for rats: C-max = 31,233 (males) or 91,300 (females) ng/ml, AUC = 11,519 (males ) or 18,620 (females) ng X hr/ml; for dogs: C-max = 9033 ng/ml, AUC = 11,094 ng X hr/ml (combined sex)] was associated with clinical patholo gic and renal histomorphologic changes considered consequent to intrav ascular hemolysis in both species, lethality and testicular toxicity i n rats, and clinical biochemical changes indicative of hepatobiliary i njury in dogs. Studies indicated that hemolysis occurred during infusi on, was not caused by circulating levels of safingol, and was a functi on of dose concentration and vein of delivery. Safingol at 10 or 20 mg /kg was administered iv to rats 30-60 min prior to myelosuppressive iv doses of DOX, CIS, or cyclophosphamide (CYP). Hematology, plus renal function and morphology for CIS-treated animals, was assessed 4 and 14 days later. Safingol did not potentiate DOX-, CIS-, or CYP-mediated l eukopenia/thrombocytopenia. A minimal enhancement of CIS-mediated decr ease in GFR and increase in creatinine was observed at 20 mg safingol/ kg. Dogs were administered 20 mg safingol/kg iv followed 60 min later by 0.5 or 1.25 mg DOX/kg or 0.75 or 2.0 mg CIS/kg. A complete toxicolo gic assessment 4 and 29 days postdose failed to show potentiation of D OX toxicity by safingol or vice versa. A renal lesion was inferred in dogs administered 20 mg/kg safingol and 2 mg/kg CIS based on minimal t o slight renal tubular regeneration observed 4 weeks post-treatment. T here were no effects of safingol on the pharmacokinetic profiles of DO X or CIS or vice versa. (C) 1995 Society of Toxicology.