Effects of frequently used pharmaceutical excipients on the organic cation transporters 1–3 and peptide transporters 1/2 stably expressed in MDCKII cells

有机阳离子转运蛋白 化学 运输机 流出 有机阴离子转运蛋白1 药理学 肌氨酸 细胞内 ATP结合盒运输机 生物化学 聚乙二醇 甘氨酸 生物 基因 氨基酸
作者
Marcus Otter,Stefan Oswald,Werner Siegmund,Markus Keiser
出处
期刊:European Journal of Pharmaceutics and Biopharmaceutics [Elsevier]
卷期号:112: 187-195 被引量:27
标识
DOI:10.1016/j.ejpb.2016.11.028
摘要

There is ample evidence that pharmaceutical excipients, which are supposed to be pharmacologically inactive, have an impact on drug metabolism and efflux transport. So far, little is known whether they also modulate uptake transporter proteins. We have recently shown that commonly used solubilizing agents exert significant effects on the function of organic anion uptake transporting polypeptides. Therefore, we investigated in this study the influence of frequently used pharmaceutical excipients on the transport activity of organic cation transporters OCT1, OCT2 and OCT3 and the peptide transporters PEPT1 and PEPT2. Inhibition of the OCTs and PEPTs by the excipients polyethylene glycol 400 (PEG), hydroxypropyl-β-cyclodextrin (HPCD), Solutol® HS15 (SOL), Cremophor® EL (CrEL), Tween® 20 (Tw20), Tween® 80 (Tw80), Kolliphor® P188 (P188) and Kolliphor® P407 (P407) was evaluated using stably transfected MDCKII cells with radio-labeled reference substrates and established inhibitors as controls. Intracellular accumulation of [3H]-1-methyl-4-phenylpyridinium (MPP+) for the OCTs and [3H]-glycyl-sarcosine (Gly-Sar) for the PEPTs was measured by liquid scintillation counting after cell lysis. Our studies revealed that PEG, HPCD, SOL, CrEL, Tw20 and Tw80 were potent inhibitors of OCT1-3 (e.g., Tw20 IC50 values < 0.04%). Cellular uptake of Gly-Sar by PEPT1 and PEPT2 was strongly inhibited by both Tw20 and Tw80. SOL was also a strong inhibitor of PEPT1 and PEPT2 (e.g., SOL IC50 values < 0.02%), while CrEL showed significantly inhibition of only PEPT2. The substantial inhibitory effects of certain solubilizing agents on OCTs and PEPTs should be considered if they are to be used in dosage forms for new chemical entities and registered drugs to avoid misinterpretation of pharmacokinetic data and undesired drug interactions.
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