Single-and Repeated-Dose Toxicity of Isophosphamide (NSC 109724) Bulk and Clinical Formulation Administered in Mice,Rats,Dogs and Monkeys.

摘要

Data are presented from four studies conducted to evaluate the toxicity of the anticancer agent, Isophosphamide, 1, 3, 2-oxazaphosphorine, 3-(2-chlorethyl)-2((2-chloroethyl) amino) tetrahydro-2-oxide (NSC 109724) in mice,rats,dogs,and rhesus monkeys. Single-dose I. V. LD50values of 427and 218mg/kg were determined for the mouse and rat,respectively. In the mouse I.P. and P.O. LD50values were calculated to be 565and 1129mg/kg x 1,and 145and 243mg/kg x 5,respectively. The drug was administered to dogs on I.V. dosage regimens of x 5and x (5(9)5),and x 14in monkeys. Lethal doses determined in the dog and monkey were 16.5mg/kg x 5,and 16.5mg/kg x 6,respectively. The highest non-toxic dose in the dog was approx. 8.25mg/kg when given as a single-dose,and 4.12and 2.06mg/kg when administered on a x 5or x (5(9)5) regimen. The highest non-toxic dose recorded for the monkey was 1.03mg/kg x 14. WBC, SGOT,and SGPT parameters appeared to be the earliest and most reliable indicators of drug toxicity. BUN was helpful only in the monkey. Dose-related hemorrhagic urinary bladders were observed in mice and dogs,but were not detected in rats or monkeys.