Uptake of lipophilic drugs by plasma derived isolated chylomicrons: Linear correlation with intestinal lymphatic bioavailability
Uptake of lipophilic drugs by plasma derived isolated chylomicrons: Linear correlation with intestinal lymphatic bioavailability
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DOI：
10.1016/j.ejps.2005.07.011
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发表时间：
2005-12-01
影响因子：
4.6
通讯作者：
Hoffman, A
中科院分区：
文献类型：
--
作者：
Gershkovich, P;Hoffman, A
药物与肠上皮细胞中乳糜微粒的结合是淋巴吸收途径中的重要步骤。在这篇文章中，亲脂性化合物的乳糜微粒离体吸收进行了比较，以阐明相关性的程度，并评估利用这种相关性作为亲脂性药物的淋巴生物利用度潜力的预测测量相应的肠淋巴生物利用度在大鼠中报道。9种亲脂性化合物（维生素D-3、维生素E、卤泛群、普罗布考、地西泮、睾酮、环孢菌素A、苯并[a]芘和pp '-DDT）以1.75 × 10（-6）M的浓度与从大鼠血液中分离的乳糜微粒乳剂孵育1小时。发现化合物与乳糜微粒的离体缔合程度与大鼠中报告的淋巴转运之间存在强线性相关性（r（2）= 0.94，P < 0.0001），而log P和在长链甘油三酯中的溶解度仅显示与淋巴生物利用度的中度相关性。分离的乳糜微粒和肠淋巴转运的化合物的摄取程度之间的线性相关性表明，这两个过程是由类似的因素。因此，亲脂性化合物与分离的乳糜微粒的缔合程度可用作估计药物分子的肠淋巴转运潜力的简单筛选模型。鉴于直接测定体内淋巴生物利用度的实际困难，这种方法是重要的。(c)2005 Elsevier B. V.保留所有权利。
Association of a drug with chylomicrons in the enterocyte is an essential step in the lymphatic absorption pathway. In this article, the uptake of lipophilic compounds by chylomicrons ex vivo was compared to the corresponding intestinal lymphatic bioavailability reported in rats in order to elucidate the degree of correlation and to evaluate the utilization of this correlation as a predictive measurement of the lymphatic bioavailability potential of lipophilic drugs. Nine lipophilic compounds (Vitamin D-3, Vitamin E, halofantrine, probucol, diazepam, testosterone, cyclosporin A, benzo[a]pyrene and pp'-DDT) at a concentration of 1.75 x 10(-6) M were incubated for I h with chylomicron emulsion separated from rat blood. A strong linear correlation was found between the degree of association of compounds with chylomicrons ex vivo and the lymphatic transport reported in rats (r(2) = 0.94, P < 0.0001), whereas log P and solubility in long chain triglycerides showed only moderate correlation with lymphatic bioavailability. The linear correlation between the degree of uptake of compounds by isolated chylomicrons and intestinal lymphatic transport suggests that the two processes are governed by similar factors. Thus, the degree of association of lipophilic compounds with isolated chylomicrons can be used as a simple screening model for estimation of intestinal lymphatic transport potential of drug molecules. This approach is important in view of the practical difficulties in direct determination of the lymphatic bioavailability in vivo. (c) 2005 Elsevier B.V. All rights reserved.