Toxicity and biodistribution of the radioprotectors, WR2721, WR77913, and WR3689, in the cns following intraventricular or intracisternal administration

Abstract

The radioprotective capacity of the phosphorothioate compounds, WR2721, WR77913, and WR3689, in the CNS is being evaluated following injection of the drugs into the lateral cerebral ventricle or the cisterna magna of F-344 rats. This approach circumvents the blood-brain barrier and permits an assessment of the CNS toxicity and regional distribution of these compounds. Following intraventricular injection in 150–200 gm female rats, the LD 50 doses for WR2721, WR77913, and WR3689 were respectively 0.60 ± 0.07 mg (S.E.), 2.36 ± 0.13 mg, and 3.56 ± 0.26 mg. Following intracisternal injection the LD 50 doses were 0.71 ± 0.18 mg, 4.12 ± 1.09 mg and 3.03 ± 0.68 mg, respectively. WR2721 produced lethargy, unsteady gait, and dishevelment but these signs all resolved completely within 1–3 days in survivors. In addition to these signs, WR77913 and WR3689 produced severe convulsions. At high doses, following intraventricular administration, all three drugs were associated with cerebral and diencephalic periventricular necrosis and ipsilateral necrosis of the lateral hippocampus. Biodistribution studies were performed with [S-35]-labeled derivatives of the drugs and tissue sampling. The three drugs demonstrated similar patterns. Forty-five minutes following either the intraventricular or intracisternal route of drug delivery the highest drug concentrations were in the brainstem, cerebellum, and cervical cord. Additional studies with autoradiography revealed that intraventricular injection was associated with high drug uptake in the cerebral white matter, the periventricular diencephalon, and the periaqueductal mesencephalon. The biodistribution and toxicity data together suggest that the drugs can be ranked, WR3689 > WR77913 > WR2721, according to the level of drug thiol that can be achieved in the CNS tissues with intraventricular or intracisternal injection. Tissue levels achievable with WR2721 following these two routes of administration are as high as levels others have reported as radioprotective in rodent skin and gut.