The role of molecular physicochemical properties and apolipoproteins in association of drugs with triglyceride-rich lipoproteins: in-silico prediction of uptake by chylomicrons
The role of molecular physicochemical properties and apolipoproteins in association of drugs with triglyceride-rich lipoproteins: in-silico prediction of uptake by chylomicrons
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DOI：
10.1211/jpp/61.01.0005
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发表时间：
2009-01-01
影响因子：
3.3
通讯作者：
Hoffman, Amnon
中科院分区：
文献类型：
--
作者：
Gershkovich, Pavel;Fanous, Joseph;Hoffman, Amnon
目的乳糜微粒对药物的摄取是肠道淋巴转运和餐后亲脂性药物处置改变的关键因素。本文的目的是阐明影响这一现象的因素。方法对22种模型亲脂分子与大鼠乳糜微粒的关联程度进行评价，并计算理化性质进行计算机关联。然后使用所有外部分子集验证了硅模型。乳糜微粒的吸收也与市场上销售的人工乳剂的关系进行了比较。发现影响乳糜微粒亲和力的最重要的理化性质是LogD(7.4)；然而，需要一个多参数模型来正确描述摄取过程。使用八个分子描述符的组合创建的硅模型((RY)-Y-2 = 0.91, （RX)-X-2 = 0.91和Q(2) = 0.82）能够成功预测外部分子集对乳糜微粒的亲和力。与人工乳化液的关联在统计上不同于乳糜微粒对9个分子中的4个分子的摄取。结论药物与乳糜微粒的关联是一个复杂的过程，涉及到亲脂核心和表面载脂蛋白。基于药物的多种物理化学性质的硅模型能够成功地预测与乳糜微粒的关联程度。
Objectives The uptake of drugs by chylomicrons is I key element ill both intestinal lymphatic transport and postprandial alterations in the disposition profile of lipophilic drugs. The aim of this article was to elucidate the factors that affect this phenomenon.Methods The degree of association of 22 model lipophilic molecules with rat chylomicrons was assessed and correlated in silico with calculated physicochemical properties. The in-silico model was then validated using all external set of molecules. The uptake by chylomicrons was also compared to the association with a marketed artificial emulsion.Key findings The most important physicochemical property that affects the affinity to chylomicrons was found to be LogD(7.4); however, a multiparameter model wits required to describe properly the uptake process. The in-silico, model ((RY)-Y-2 = 0.91, (RX)-X-2 = 0.91 and Q(2) = 0.82) that was created using a combination of eight molecular descriptors enabled Successful Prediction Of the affinity of the external set of Molecules to chylomicrons. The association with the artificial emulsion was statistically different from the uptake by chylomicrons for four (out of nine) molecules.Conclusions The association of drugs With chylomicrons is a complex process, which involves the lipophilic core as well as surface apoproteins. The in-silico model based on multiple physicochemical properties of the drugs is able to predict successfully the degree of association with chylomicrons.