Lawless Emma, Griffin Brendan T, O'Mahony Aoife, O'Driscoll Caitriona M
School of Pharmacy, Trinity College Dublin, Dublin 2, Ireland.
Pharm Res. 2015 May;32(5):1817-29. doi: 10.1007/s11095-014-1578-x. Epub 2014 Nov 27.
Intestinal lymphatic transport of specific lipophilic drugs offers therapeutic advantages and maximises oral bioavailability. The aims of this study were; to compare intestinal lymphatic transport of a range of drugs and to investigate the influence of cyclosporine A on the mechanism/extent of lymphatic transport.
Caco2 cells and an anaesthetised mesenteric lymphatic cannulated rat model were used for in vitro and in vivo studies. Lymphatic transport of three lipophilic drugs was directly compared in a long chain fatty acid formulation. In addition, the impact of cyclosporine A on triglyceride turnover was evaluated in vivo and in vitro.
The extent of intestinal lymphatic transport in rats was positively correlated with drug solubility in triglyceride and negatively correlated with drug aqueous solubility. Cyclosporine A displayed non-linear lymphatic transport kinetics and reduced intestinal lymph triglyceride. In vitro experiments indicated that the cellular processes affected were intracellular lipid processing and/or lipid secretion.
The linear correlations obtained using a range of lipophilic drugs confirm that the simplified approach of determining aqueous or triglyceride drug solubility is useful in predicting the extent of lymphatic transport. In vitro experiments correlated with in vivo observations, demonstrating the usefulness of the Caco-2 model for mechanistic investigations.
特定亲脂性药物的肠道淋巴转运具有治疗优势，并能使口服生物利用度最大化。本研究的目的是：比较一系列药物的肠道淋巴转运，并研究环孢素A对淋巴转运机制/程度的影响。
采用Caco2细胞和麻醉的肠系膜淋巴插管大鼠模型进行体外和体内研究。在长链脂肪酸制剂中直接比较了三种亲脂性药物的淋巴转运。此外，在体内和体外评估了环孢素A对甘油三酯周转的影响。
大鼠肠道淋巴转运程度与药物在甘油三酯中的溶解度呈正相关，与药物的水溶性呈负相关。环孢素A表现出非线性淋巴转运动力学，并降低了肠道淋巴甘油三酯。体外实验表明，受影响的细胞过程是细胞内脂质加工和/或脂质分泌。
使用一系列亲脂性药物获得的线性相关性证实，确定药物水溶性或甘油三酯溶解度的简化方法有助于预测淋巴转运程度。体外实验与体内观察结果相关，证明了Caco-2模型在机制研究中的有用性。
