Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60)-63-tris Malonic Acid[C3] in Mice and Primates.

Abstract

Fullerene-based compounds are a novel class of molecules being developed for a variety of biomedical applications, with nearly 1000 publications in this area in the last 4years alone. One such compound, the e,e,e-methanofullerene(60)-63-tris malonic acid (designatedC3), is a potent catalytic superoxide dismutase mimetic which has shown neuroprotective efficacy in a number of animal models of neurologic disease, including Parkinsonian Macaca fascicularis monkeys.The aim of this study was tocharacterize its toxicity and pharmacokinetics in mice and monkeys. To assess pharmacokinetics in mice, we synthesized and administered 14C-C3 to mice using various routes of delivery, including orally. To assess potential toxicity in primates, serial blood studies and electrocardiograms (ECGs) were obtained from monkeys treated with C3 (3 or 7mg/kg/day) for 2 months. The plasma half-life of C3was 8.2±0.2h, and there was wide tissue distribution, including uptake into brain. The compound was cleared by both hepatic and renal excretion. C3 was quite stable, with minimal metabolism of the compound even after 7days of treatment. The LD50 in mice was 80mg/kg for a single intraperitoneal injection, and was >30mg/kg/day for sustained administration; therapeutic doses are 1-5mg/kg/day. For primates, no evidence of renal, hepatic, electrolyte, or hematologic abnormalities were noted, and serial ECGs demonstrated no alteration in cardiac electrical activity. Thus, doses of C3 that have therapeutic efficacy appear to be well tolerated after 2years (mice) or 2months (non-human primates) of treatment.