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

Background And Objectives: 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 4 years alone. One such compound, the e,e,e-methanofullerene(60)-63-tris malonic acid (designated C), 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 to characterize its toxicity and pharmacokinetics in mice and monkeys.

Methods: To assess pharmacokinetics in mice, we synthesized and administered C-C 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 C (3 or 7 mg/kg/day) for 2  months.

Results And Conclusions: The plasma half-life of C was 8.2 ± 0.2 h, and there was wide tissue distribution, including uptake into brain. The compound was cleared by both hepatic and renal excretion. C was quite stable, with minimal metabolism of the compound even after 7 days of treatment. The LD in mice was 80 mg/kg for a single intraperitoneal injection, and was > 30 mg/kg/day for sustained administration; therapeutic doses are 1-5 mg/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 C that have therapeutic efficacy appear to be well tolerated after 2 years (mice) or 2 months (non-human primates) of treatment.