Improved nonclinical pharmacokinetics and biodistribution of a new PPAR pan-agonist and COX inhibitor in nanocapsule formulation
Improved nonclinical pharmacokinetics and biodistribution of a new PPAR pan-agonist and COX inhibitor in nanocapsule formulation
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DOI：
10.1016/j.jconrel.2015.04.033
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发表时间：
2015-07-10
影响因子：
10.8
通讯作者：
Furtado Mosqueira, Vanessa Carla
中科院分区：
文献类型：
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作者：
Garcia, Giani Martins;Oliveira, Liliam Teixeira;Furtado Mosqueira, Vanessa Carla
我们报道了一种新的过氧化物酶体增殖物激活受体- γ激动剂和游离或与聚D， l -乳酸相关的环氧化酶抑制剂（Lyso-7）在小鼠静脉注射后的体外释放谱、比较药代动力学和生物分布。Lyso-7属于一类胰岛素增敏剂，在糖尿病治疗中显示出潜在的有益作用。单分散lyso - 7nc平均粒径为273 nm，包封率高达83%。在NC中加载后，Lyso-7的溶出率降低了2.6倍。采用非室室法测定药代动力学参数。与溶液中的Lyso-7相比，Lyso-7- nc的血浆auc增加了14倍，平均停留时间增加2.6倍，平均半衰期（t(1/2)）增加1.5倍；血浆中Lyso-7的清除率、分布体积和清除率分别降低了13倍、10倍和1.4倍，表明包裹Lyso-7在血室中的滞留率较高。与NC相关，与溶液中的Lyso-7相比，心脏（3.6倍）、肺（2.8倍）、脾脏（2.3倍）、肾脏（2倍）和肝脏（1.8倍）的器官暴露量更高。对整个数据的分析清楚地表明，纳米胶囊化后，人体暴露于Lyso-7的程度增加，总体毒性降低，从而可以在非临床和临床研究中进一步评估Lyso-7。(C) 2015 Elsevier B.V.版权所有
We report the in vitro release profile and comparative pharmacokinetics and biodistribution of a new peroxisome proliferator-activated receptor-gamma agonist and cyclooxygenase inhibitor (Lyso-7) free or associated to poly(D, L-lactic acid) nanocapsules (NC) after intravenous administration in mice. Lyso-7 pertains to the class of insulin-sensitizing agents that shows potential beneficial effects in diabetes therapy. Monodispersed Lyso-7 NC with a mean diameter of 273 nm with high encapsulation efficiency (83%) were obtained. Lyso-7 dissolution rate was reduced (2.6-fold) upon loading in NC. The pharmacokinetic parameters were determined using a non-compartmental approach. In comparison with Lyso-7 in solution, the plasma-AUC increased 14-fold, the mean residence time 2.6-fold and the mean half-life (t(1/2)) 1.5-fold for Lyso-7-NC; the Lyso-7 plasma clearance, distribution volume and elimination rate were reduced 13, 10 and 1.4 fold, respectively, which indicates higher retention of encapsulated Lyso-7 in the blood compartment. Upon association with NC, organ exposure to Lyso-7 was higher in the heart (3.6-fold), lung (2.8-fold), spleen (2.3-fold), kidney (2-fold) and liver (1.8-fold) compared to Lyso-7 in solution. The analysis of whole data clearly indicates that body exposure to Lyso-7 was enhanced and the general toxicity reduced upon nanoencapsulation, allowing further evaluation of Lyso-7 in nonclinical and clinical studies. (C) 2015 Elsevier B.V. All rights reserved.