title: Effects of frequently used pharmaceutical excipients on the organic cation transporters 1-3 and peptide transporters 1/2 stably expressed in MDCKII cells.
abstract: 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 IC50values<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 IC50values<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.
authors.affiliation: Department of Clinical Pharmacology, University Medicine, Greifswald, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Otter
authors.affiliation: Department of Clinical Pharmacology, University Medicine, Greifswald, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Oswald
authors.affiliation: Department of Clinical Pharmacology, University Medicine, Greifswald, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Siegmund
authors.affiliation: Department of Clinical Pharmacology, University Medicine, Greifswald, Germany. Electronic address: markus.keiser@uni-greifswald.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Keiser
mesh_terms: D000818:Animals; D004285:Dogs; D005079:Excipients; D005455:Fluorescent Antibody Technique; D061985:Madin Darby Canine Kidney Cells; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D005079:Excipients; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger
keywords: Cell model; Competition assay; Cremophor; Drug transporter; Hydroxypropyl-β-cyclodextrin; In vitro; Inhibition assay; Kolliphor (poloxamer); MDCK cells; Organic cation transporter (OCT); Peptide transporter (PEPT); Pharmaceutical excipients; Polyethylene glycol (PEG); Solubilizing agents; Solutol HS 15 (macrogol 15 hydroxystearate, polyoxyl 15 hydroxystearate); Tween (polysorbate); Uptake transport