A multiple-dose pharmacokinetics of polyethylene glycol recombinant human interleukin-6 (PEG-rhIL-6) in rats
A multiple-dose pharmacokinetics of polyethylene glycol recombinant human interleukin-6 (PEG-rhIL-6) in rats
复制标题
聚乙二醇重组人白细胞介素6（PEG-rhIL-6）在大鼠体内的多剂量药代动力学
DOI：
10.1631/jzus.b1000085
复制
发表时间：
2011-01-01
影响因子：
5.1
通讯作者：
Zhang, Xue-mei
中科院分区：
文献类型：
--
作者：
He, Xue-ling;Yin, Hai-lin;Zhang, Xue-mei
放射治疗已广泛应用于癌症治疗。然而，它常常作为一种不良反应导致血小板减少症（白细胞缺乏）。重组人白细胞介素 - 6（rhIL - 6）已被发现是一种对抗这种血小板减少症非常有效的方法，但白细胞介素 - 6在血液中的稳定性较低，这降低了其疗效。为了增加rhIL - 6的稳定性和半衰期，用聚乙二醇（PEG）对其进行了修饰。在大鼠皮下注射用I - 125标记的PEG - rhIL - 6后，对其药代动力学和组织分布进行了检测。PEG - rhIL - 6的药代动力学模式呈线性动力学，我们拟合了一个单室模型，在大鼠体内其吸收半衰期t(1/2K)(a)为10.44 - 11.37小时，消除半衰期t(1/2Ke)为19.77 - 21.53小时，达峰时间t(peak)为20.51 - 21.96小时。PEG - rhIL - 6的半衰期和达峰时间比先前报道的rhIL - 6更长。在本研究中，对于PEG - rhIL - 6在大鼠体内的沉积，组织分布检测显示主要涉及的器官是血液，而非肝脏。然而，就PEG - rhIL - 6的消除而言，主要器官是肾脏。皮下给药192小时后，从尿液中回收的注射剂量的排泄分数为23.32%。在192小时时，通过粪便消除的PEG - rhIL - 6不到6%。这些结果表明，PEG - rhIL - 6是癌症患者的一种良好的候选药物制剂。
Radiation therapy has been widely applied in cancer treatment. However, it often causes thrombocytopenia (deficiency of white blood cells) as an adverse effect. Recombinant human interleukin-6 (rhIL-6) has been found to be a very effective way against this thrombocytopenia, but IL-6 has low stability in blood, which reduces its efficacy. To increases the stability and half-life of rhIL-6, it was modified by polyethylene glycol (PEG). The pharmacokinetics and the tissue distribution of PEG-rhIL-6 labeled with125I were examined after subcutaneous injection in rats. The pharmacokinetic pattern of PEG-rhIL-6 was defined with linear-kinetics, and we fitted a one-compartment model with half-lives of 10.44–11.37 h (absorption,t1/2Ka) and 19.77–21.53 h (elimination,t1/2Ke), and peak concentrations at 20.51–21.96 h (tpeak) in rats. Half-lives andtpeakof PEG-rhIL-6 were longer than those of rhIL-6 previously reported. In the present study, for deposition of PEG-rhIL-6 in rats, the tissue distribution examination showed that blood was the major organ involved, rather than liver. However, as to the elimination of PEG-rhIL-6, the major organ was the kidney. The excretion fraction of the injection dose recovered from urine was 23.32% at 192 h after subcutaneous administration. Less than 6% of PEG-rhIL-6 was eliminated via the feces at 192 h. These results indicate that PEG-rhIL-6 is a good candidate drug formulation for patients with cancer.