Pharmacokinetics of a water-soluble fullerene in rats

被引:85
作者
Rajagopalan, P
Wudl, F
Schinazi, RF
Boudinot, FD
机构
[1] UNIV GEORGIA,COLL PHARM,DEPT PHARMACEUT,ATHENS,GA 30602
[2] UNIV CALIF SANTA BARBARA,INST POLYMERS & ORGAN SOLIDS,SANTA BARBARA,CA 93106
[3] UNIV CALIF SANTA BARBARA,DEPT CHEM,SANTA BARBARA,CA 93106
[4] UNIV CALIF SANTA BARBARA,DEPT PHYS,SANTA BARBARA,CA 93106
[5] VET AFFAIRS MED CTR,DECATUR,GA 30033
[6] EMORY UNIV,SCH MED,DEPT PEDIAT,BIOCHEM PHARMACOL LAB,ATLANTA,GA 30322
关键词
D O I
10.1128/AAC.40.10.2262
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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-C-60 (MSAD-C-60) is a water-soluble fullerene derivative. MSAD-C-60 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-C-60 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 C-60 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-C-60 in plasma declined either bi- or triexponentially, The mean terminal-phase half-life of MSAD-C-60 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 liters/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-C-60 averaged 2.1 +/- 0.8 liters/kg, indicating that the compound distributes into tissues, At a dose of 15 mg/kg, MSAD-C-60 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.
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收藏
页码:2262 / 2265
页数:4
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