Pharmacokinetics of a water-soluble fullerene in rats
Pharmacokinetics of a water-soluble fullerene in rats
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DOI：
10.1128/aac.40.10.2262
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发表时间：
1996-10-01
影响因子：
4.9
通讯作者：
Boudinot, FD
中科院分区：
文献类型：
--
作者：
Rajagopalan, P;Wudl, F;Boudinot, FD
富勒烯是近年来发现的碳的第三种同素异形体，其生物活性的研究正处于各个方面。对，对′-二（2-氨基乙基）-二苯基-C-60的双（单琥珀酰亚胺）衍生物（MSAD-C-60）是一种水溶性富勒烯衍生物。MSAD-C-60已显示在体外具有抗人类免疫缺陷病毒1型和2型的抗病毒活性，并具有杀病毒和抗人类免疫缺陷病毒蛋白酶活性。此外，MSAD-C-60已显示在腹膜内给药后在小鼠中耐受良好。本研究的目的是开发MSAD C-60的高效液相色谱分析方法，并表征该化合物在大鼠中的临床前药代动力学。在以15 mg/kg体重的剂量静脉内施用富勒烯衍生物后，血浆中MSAD-C-60的浓度呈双指数或三指数下降，MSAD-C-60的平均终末相半衰期为6.8 +/- 1.1 h（平均值+/-标准差）。结合研究表明，该化合物与血浆蛋白的结合率大于99%。该化合物的平均总清除率为0.19 +/- 0.06 L/h/kg。静脉内给药后24小时获得的尿样不含可检测水平的化合物，表明不存在显著的肾清除机制。MSAD-C-60的稳态分布容积平均为2.1 +/-0.8升/kg，表明化合物分布到组织中。在15 mg/kg的剂量下，MSAD-C-60似乎耐受良好。25 mg/kg的剂量导致大鼠呼吸急促和剧烈运动，随后在给药后5分钟内死亡。需要进一步的对照毒性研究以充分评价该化合物的毒性。
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.