gms | German Medical Science

Aim: There is ample evidence that pharmaceutical excipients which are supposed to be pharmacologically inactive by definition may significantly influence drug metabolism and efflux transport. So far, little is known about their impact on uptake transport proteins. Therefore, we investigated the influence of frequently used polyethylene glycol 400 (PEG), hydroxypropyl-β-cyclodextrin (HPCD), Solutol^® HS15 (SOL), Cremophor^® EL (CrEL), Tween^® 20 / 80 and Kolliphor^® P188 / P407 on the function of peptide transporter (PEPT) 1 and 2 and on organic cation transporter (OCT) 1, 2 and 3.

Method: Inhibitory effects of the excipients were studied in competition assays using MDCKII cells stably transfected with the above-mentioned transporters and established radio-labelled reference substrates and inhibitors. Intracellular accumulation of [³H]-glycyl-sarcosine (Gly-Sar) for peptide transporters and [3H]-1-methyl-4-phenylpyridinium (MPP) for organic cation transporters was measured by liquid scintillation counting after cell lysis.

Results: PEG, HPCD, SOL, CrEL, Tween^® 20 and 80 were potent inhibitors of OCT 1–3 (e.g. Tween^® 20 with IC(50) values <0.02%). Uptake of Gly-Sar by PEPT1 and PEPT2 was strongly inhibited in presence of Tween^® 20 and 80. CrEL and SOL were also potent inhibitors of PEPT2-mediated uptake of Gly-Sar (e.g. SOL with IC(50) value of 0.01%).

Conclusion: The investigated solubilizing agents demonstrated substantial effects on the function of PEPT1/2 and OCTs localized to the intestine, liver and kidneys, respectively. These effects should be considered in preclinical drug development. However, the clinical relevance should be evaluated in further investigations.