Lb. Kedderis et al., TOXICITY OF THE PROTEIN-KINASE-C INHIBITOR SAFINGOL ADMINISTERED ALONE AND IN COMBINATION WITH CHEMOTHERAPEUTIC-AGENTS, Fundamental and applied toxicology, 25(2), 1995, pp. 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 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.