Toxicity of the Protein Kinase C Inhibitor Safingol Administered Alone and in Combination with Chemotherapeutic Agents

• Published in: Fundamental and applied toxicology 1995-05, Vol.25 (2), p.201-217
• Main Authors: Kedderis, Lorrene Buckley, Bozigian, Haig P., Kleeman, James M., Hall, Robert L., Palmer, Thomas E., Harrison, Steadman D., Susick, Robert L.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cisplatin - pharmacokinetics; Cisplatin - toxicity; Cyclophosphamide - pharmacokinetics; Cyclophosphamide - toxicity; Dogs; Dose-Response Relationship, Drug; Doxorubicin - pharmacokinetics; Doxorubicin - toxicity; Drug Synergism; Drug toxicity and drugs side effects treatment; Female; Hemolysis - drug effects; Injections, Intravenous; Kidney - pathology; Kidney Tubules - pathology; Liver - drug effects; Liver - pathology; Male; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Necrosis; Pharmacology. Drug treatments; Protein Kinase C - antagonists & inhibitors; Rabbits; Rats; Rats, Sprague-Dawley; Sphingosine - administration & dosage; Sphingosine - analogs & derivatives; Sphingosine - blood; Sphingosine - toxicity; Testis - drug effects; Testis - pathology
• ISSN: 0272-0590; 1095-6832
• DOI: 10.1006/faat.1995.1056

Toxicity of the Protein Kinase C Inhibitor Safingol Administered Alone and in Combination with Chemotherapeutic Agents. Kedderis, L. B., Bozigian, H. P., Kleeman, J. M., Hall, R. L., Palmer, T. E., Harrison, S. D., Jr., and Susick, R. L., Jr. (1995). Fundam. Appl. Toxicol. 25, 201-217. 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 evaluate safingol toxicity when administered iv as a single agent and to evaluate safingol's ability to potentiate the toxicity of established chemotherapeutic agents to normal tissues in vivo. In an escalating dose study, dogs were administered safingol iv at 5, 10, 20, 30, 40, and 75 mg/kg on Days 1 through 6. Necropsies were performed on Day 7. Red urine was observed at 10 mg/kg and higher. Icterus was observed following 40 mg/kg with additional signs of hypoactivity and anorexia occurring after 75 mg/kg. Clinical and microscopic pathology revealed marked hepatotoxicity, venous degeneration and necrosis at injection sites, and evidence of intravascular hemolysis. Doses of 5, 20, or 40 mg safingol/kg were utilized in single iv dose rat and dog studies. No evidence of adverse systemic toxicity was seen up to 20 mg/kg in either species [for rats: C max = 12,600 (males) or 17,133 (females) ng/ml, AUC = 3853 (males) or 4365 (females) ng × hr/ml; for dogs: C max = 2533 ng/ml, AUC = 2851 ng × hr/ml (no sex differences)]. Local effects of venous 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 × hr/ml; for dogs: C max = 9033 ng/ml, AUC = 11,094 ng × hr/ml (combined sex)] was associated with clinical pathologic and renal histomorphologic changes considered consequent to intravascular hemolysis in both species, lethality and testicular toxicity in rats, and clinical biochemical changes indicative of hepatobiliary injury in dogs. Studies indicated that hemolysis occurred during infusion, was not caused by circulating levels of safingol, and was a function of dose concentration and vein of delivery. Safingol at 10 or 20 mg/kg was administered iv to rats 30-60 rain prior to myelosuppressive iv doses of DOX, CIS, or cyclophosphamide (CYP). Hematology, plus renal function and morphology for CIS-treated a