Intestinal permeability enhancement of levothyroxine sodium by straight chain fatty acids studied in MDCK epithelial cell line

Abstract

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 ≈ 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.