Renal tubular secretion of pramipexole
Knop J, Hoier E, Ebner T, Fromm M, Müller F (2015)
Publication Type: Journal article
Publication year: 2015
Journal
Publisher: Elsevier
Book Volume: 79
Pages Range: 73-8
DOI: 10.1016/j.ejps.2015.09.004
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 12?M and 5.5?M 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 with CRIS profile
Jana Knop
Lehrstuhl für Biochemie und Pathobiochemie
Martin Fromm
Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie
Fabian Müller
Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie
Involved external institutions
Germany (DE)How to cite
APA:
Knop, J., Hoier, E., Ebner, T., Fromm, M., & Müller, F. (2015). Renal tubular secretion of pramipexole. European Journal of Pharmaceutical Sciences, 79, 73-8. https://dx.doi.org/10.1016/j.ejps.2015.09.004
MLA:
Knop, Jana, et al. "Renal tubular secretion of pramipexole." European Journal of Pharmaceutical Sciences 79 (2015): 73-8.
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