University of Rhode Island, Kingston, 02881, USA.
Eur J Pharm Sci. 2010 Aug 11;40(5):466-72. doi: 10.1016/j.ejps.2010.05.002. Epub 2010 May 16.
Levothyroxine sodium (T4), administered orally, is used for the treatment of hypothyroidism. T4 is a narrow therapeutic index drug with highly variable bioavailability (40-80%). The purpose of the present study was to increase the transepithelial transport of T4 using straight chain fatty acids across Madin-Darby Canine kidney (MDCK) cell line. Capric acid (C10), lauric acid (C12) and oleic acid (C18) were studied in molar ratios of 1:0.5, 1:1, 1:2 and 1:3 (T4:fatty acid). Transport of the hydrophilic marker, Lucifer yellow, was also studied. All three fatty acids proved to significantly increase T4 transport and the order of enhancement was to the effect of C12 approximately C18>C10. This Increase in transport was accompanied by reductions in transepithelial electrical resistance (TEER) values, which indicates an opening of tight junctions. Cytotoxic effects of the fatty acids were evaluated by TEER measurements, lactate dehydrogenase release, percent viability and propidium iodide staining of the cells. At the lower molar concentrations of 1:1, the fatty acids did not show any toxicity. However, C12 and C18 when added, to T4:fatty acid molar ratio of 1:2 and 1:3, respectively showed severe toxicity with irreversible damage to the cells. Hence, addition of fatty acids to T4 formulations at low concentrations can significantly improve intestinal permeability of T4 without any toxicity potentially leading to improved bioavailability.
左甲状腺素钠（T4）经口给药，用于治疗甲状腺功能减退症。T4 是一种治疗指数较窄、生物利用度变化较大（40-80%）的药物。本研究旨在通过使用直链脂肪酸增加 T4 经 Madin-Darby 犬肾（MDCK）细胞系的跨上皮转运。研究了癸酸（C10）、月桂酸（C12）和油酸（C18），摩尔比分别为 1:0.5、1:1、1:2 和 1:3（T4：脂肪酸）。还研究了亲水性标记物荧光素黄的转运。所有三种脂肪酸都被证明能显著增加 T4 的转运，增强效果的顺序为 C12 约 C18>C10。这种转运增加伴随着跨上皮电阻（TEER）值的降低，表明紧密连接的开放。通过 TEER 测量、乳酸脱氢酶释放、细胞活力百分比和碘化丙啶染色评估脂肪酸的细胞毒性。在较低的摩尔浓度 1:1 下，脂肪酸没有显示出任何毒性。然而，当 C12 和 C18 分别以 T4:脂肪酸摩尔比 1:2 和 1:3 添加到 T4 中时，表现出严重的毒性，对细胞造成不可逆的损伤。因此，在低浓度下向 T4 制剂中添加脂肪酸可以显著提高 T4 的肠道通透性，而不会产生任何潜在导致生物利用度提高的毒性。
