Renal tubular secretion of pramipexole

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• 作者：Jana Knop^a ; Eva Hoier^a ; Thomas Ebner^b ; Martin F. Fromm^a ; ^{martin.fromm@fau.de" class="auth_mail" title="E-mail the corresponding author} ; Fabian Mü ; ller^a ; ¹
• 关键词：MATE ; OCT2 ; Cimetidine ; Drug transport ; MDCK
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2015
• 出版时间：15 November 2015
• 年：2015
• 卷：79
• 期：Complete
• 页码：73-78
• 全文大小：590 K

文摘

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 渭M and 5.5 渭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.