多元醇对Caco-2细胞的通透性及其对低通透性药物转运的影响

D. Truffin, O. Häusler, Mary Martin, S. Cotier, J. Laparre, Manilduth Ramnath
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引用次数: 0

摘要

一些药用辅料能够改变肠道通透性,从而影响药物的吸收和生物利用度。采用Caco-2细胞渗透性模型,研究了甘露醇、麦芽糖醇、山梨醇和木糖醇四种多元醇对代表不同BCS类别(呋塞米、阿米洛利、阿替洛尔、雷尼替丁、纳多洛尔、l -甲状腺素和阿昔洛韦)七种活性药物成分(API)渗透性的影响。建立了超高效液相色谱-三重四极杆质谱联用技术(UHPLC-QqQ)对多元醇和原料药的定量分析方法。表观渗透性系数(Papp)是由测量的浓度在根尖室和基底室计算。在所有试验中,细胞单层在整个实验过程中保持完整,既没有发现明显的路西法黄(LY)传代,也没有检测到电阻的修饰,这表明没有活性原理或辅料(或其组合)调节细胞旁运输。将药物+赋形剂组合的根尖至基底外侧、基底外侧至根尖方向的Papp值与单用原料药的Papp值进行比较。结果表明,甘露醇、麦芽糖醇、山梨醇和木糖醇对呋塞米、阿米洛利、阿替洛尔、雷尼替丁、纳多洛尔、阿昔洛韦和l -甲状腺素原料药的渗透性没有影响。此外,多元醇的存在并没有改变活性原理(基底外侧到根尖)的流出。
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Polyols Permeability on Caco-2 Cells and Their Effects on Transport of Low-Permeability Drugs
Some pharmaceutical excipients are able to modify intestinal permeability, thus influencing drug absorption and bioavailability. The effect of four polyols (mannitol, maltitol, sorbitol and xylitol) on the permeability of seven active pharmaceutical ingredients (API), representing different BCS classes (furosemide, amiloride, atenolol, ranitidine, nadolol, L-thyroxine and acyclovir), was investigated using the Caco-2 cell permeability model. Analytical methods for the sensitive polyol and API quantification were developed using Ultra High Performance Liquid Chromatography coupled to triple-quadrupole Mass Spectrometry (UHPLC-QqQ). Apparent permeability coefficients (Papp) were calculated from the measured concentrations in the apical and basolateral compartments. The cell monolayer remained intact throughout the experiment in all trials, neither significant Lucifer Yellow (LY) passage, nor modification of the electrical resistance was detected, demonstrating that no active principle or excipient (or combinations thereof) modulated the paracellular transport. The Papp values for apical to basolateral and basolateral to apical directions of drug + excipient combinations were compared with the Papp values for the drug substance alone. Our results show that mannitol, maltitol, sorbitol and xylitol did not modify the permeability of furosemide, amiloride, atenolol, ranitidine, nadolol, acyclovir and L-thyroxine APIs. Moreover, the presence of polyols did not alter the efflux of the active principle (basolateral to apical).
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