Evaluating the toxicity of novel Zn-DTPA tablet formulation in dogs and rats.

The purpose of this research work is to evaluate toxicity of diethylenetriamine pentaacetic acid zinc trisodium salt (Zn-DTPA) tablets, a novel oral solid dosage form containing permeation enhancers in beagle dogs and Sprague Dawley rats. (Zn-DTPA) in tablet dosage form was administered once daily for 7 days to beagle dogs at low (840 mg/dog/day), mid (2520 mg/dog/day), or high (7560 mg/dog/day). On day 8, all treated and control groups were necropsied. The novel Zn-DTPA tablet formulation showed rapid absorption with the T(max) at 1 h. Plasma concentrations as high as 270 μg/mL were observed after 7 days of administration. Exposure to DTPA, based on area under the curve (AUC(last)) and maximum concentration (C(max)), was dose dependent but not dose proportional. No biologically relevant changes in hematology or clinical chemistry that were related to DTPA exposure were observed, and there were no changes in body weight in treated dogs compared with controls. Zn-DTPA was well tolerated, with minor toxicological effects of emesis and diarrhea, following oral tablet administration for 7 consecutive days. Based on the endpoints evaluated in this study, the maximum tolerated dose is considered to be greater than 7560 mg/dog/day (2535 μmol/kg/day, 1325 mg/kg/day), and the no-observed-adverse-effect level (NOAEL) is considered to be approximately 1325 mg/kg/day per oral when given to male and female beagle dogs. For rats, the NOAEL was estimated to be greater than 1000 mg/kg/day when administered by oral gavage of the crushed Zn-DTPA tablets as suspension once daily (qd) to male and female Sprague Dawley rats.