title: Renal tubular secretion of pramipexole.
abstract: The dopamine agonist pramipexole is cleared predominantly by the kidney with a major contribution of active renal secretion. Previously the organic cation transporter 2 (OCT2) was shown to be involved in the uptake of pramipexole by renal tubular cells, while the mechanism underlying efflux into tubular lumen remains unclear. Cimetidine, a potent inhibitor of multidrug and toxin extrusion proteins 1 (MATE1) and 2-K (MATE2-K), decreases renal pramipexole clearance in humans. We hypothesized that, in addition to OCT2, pramipexole may be a substrate of MATE-mediated transport. Pramipexole uptake was investigated using MDCK or HEK cells overexpressing OCT2, MATE1 or MATE2-K and the respective vector controls (Co). Transcellular pramipexole transport was investigated in MDCK cells single- or double-transfected with OCT2 and/or MATE1 and in Co cells, separating a basal from an apical compartment in a model for renal tubular secretion. Pramipexole uptake was 1.6-, 1.1-, or 1.6-folds in cells overexpressing OCT2, MATE1 or MATE2-K, respectively as compared to Co cells (p<0.05). In transcellular transport experiments, intracellular pramipexole accumulation was 1.7-folds in MDCK-OCT2 (p<0.001), and transcellular pramipexole transport was 2.2- and 4.0-folds in MDCK-MATE1 and MDCK-OCT2-MATE1 cells as compared to Co cells (p<0.001). Transcellular pramipexole transport was pH dependent and inhibited by cimetidine with IC50 values of 12μM and 5.5μM in MATE1 and OCT2-MATE1 cells, respectively. Taken together, coordinate activity of OCT2-mediated uptake and MATE-mediated efflux determines pramipexole renal secretion. Reduced OCT2 or MATE transport activity due to genetic variation or drug-drug interactions may affect pramipexole renal secretion.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Knop
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Hoier
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebner
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: martin.fromm@fau.de.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D002927:Cimetidine / Q000494:pharmacology; D004285:Dogs; D018491:Dopamine Agonists / Q000493:pharmacokinetics*; D057809:HEK293 Cells / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells / Q000378:metabolism; D000077487:Pramipexole
chemical_list: D052160:Benzothiazoles; D018491:Dopamine Agonists; D002927:Cimetidine; D000077487:Pramipexole
keywords: Cimetidine; Drug transport; MATE; MDCK; OCT2