Pharmacokinetics of a water-soluble fullerene in rats.
Fullerenes are the recently discovered third allotropic form of carbon. The biological activities of these compounds are being studied for various purposes. The bis(monosuccinimide) derivative of p p'-bis(2-amino-ethyl)-diphenyl-C60 (MSAD-C60) is a water-soluble fullerene derivative. MSAD-C60 has been shown to have antiviral activity against human immunodeficiency virus types 1 and 2 in vitro and to have virucidal and anti-human immunodeficiency virus protease activities. Moreover, MSAD-C60 has been shown to be well tolerated in mice after intraperitoneal administration. The purpose of the present study was to develop a high-performance liquid chromatographic analytical methodology for MSAD-C60 and to characterize the preclinical pharmacokinetics of the compound in rats. Following intravenous administration of the fullerene derivative at a dose of 15 mg/kg of body weight, the concentrations of MSAD-C60 in plasma declined either bi- or triexponentially. The mean terminal-phase half-life of MSAD-C60 was 6.8 +/- 1.1 h (mean +/- standard deviation). Binding studies indicated that the compound is greater than 99% bound to plasma proteins. The average total clearance of the compound was 0.19 +/- 0.06 liter/h/kg. Urine samples obtained 24 h after intravenous administration did not contain detectable levels of the compound, indicating the absence of a significant renal clearance mechanism. The steady-state volume of distribution of MSAD-C60 averaged 2.1 +/- 0.8 liters/kg, indicating that the compound distributes into tissues. At a dose of 15 mg/kg, MSAD-C60 appeared to be well tolerated. However, a dose of 25 mg/kg resulted in shortness of breath and violent movement of the rats, followed by death within 5 min of dosing. Further controlled toxicity studies are needed to fully evaluate the toxicity of the compound.
Rajagopalan
P
P
Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602, USA.
Wudl
F
F
Schinazi
R F
RF
Boudinot
F D
FD
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002244:Carbon / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D037741:Fullerenes; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D019380:Anti-HIV Agents; D037741:Fullerenes; D002244:Carbon; C069837:fullerene C60