ORCID Profile
0000-0001-7016-5482
Current Organisation
Friedrich-Alexander-Universität Erlangen-Nürnberg
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Publisher: Springer Science and Business Media LLC
Date: 07-2020
DOI: 10.1007/S00726-020-02867-8
Abstract: Elevated plasma concentrations of the uremic toxin asymmetric dimethylarginine (ADMA) and low plasma concentrations of l -homoarginine are independently associated with cardiovascular events and mortality. Key enzymes involved in the homeostasis of both arginine derivatives are expressed in proximal tubule cells of the kidney. To get access to these enzymes, transport proteins are important. One of the transporters mediating the transport of ADMA and l -homoarginine is the solute carrier superfamily (SLC) member OATP4C1, located in the basolateral membrane of proximal tubule cells. To gain insights into the role of export pumps in the transport of both substances, we established a double-transfected MDCK cell line expressing OATP4C1 and the export pump P-glycoprotein (P-gp). Using MDCK cell monolayers, we demonstrated in time-dependent and concentration-dependent vectorial transport experiments that ADMA and l -homoarginine are transported from the basolateral to the apical compartment of MDCK-OATP4C1-P-gp cells with significantly higher transport rates compared to single-transfected MDCK-OATP4C1, MDCK-P-gp and MDCK-VC (control) cells (e.g. transport ratio MDCK-OATP4C1-P-gp/MDCK-VC: for 50 µM ADMA = 2.0-fold, for 50 µM l -homoarginine = 3.4-fold). These results indicate that both OATP4C1 and P-gp transport the arginine derivatives ADMA and l -homoarginine and are, therefore, important for the homoeostasis of both substances.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 27-09-2022
DOI: 10.1124/MOLPHARM.122.000539
Abstract: Cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3), a splice variant of the hepatic uptake transporter OATP1B3 (liver-type Lt-OATP1B3), is expressed in several tumor entities including colorectal carcinoma (CRC) and breast cancer. In CRC, high OATP1B3 expression has been associated with reduced progression-free and overall survival. Several kinase inhibitors used for antitumor treatment are substrates and/or inhibitors of OATP1B3 (e.g. encorafenib, vemurafenib). The functional importance of Ct-OATP1B3 has not been elucidated so far. HEK293 cells stably overexpressing Ct-OATP1B3 protein were established and compared with control cells. Confocal laser scanning microscopy, immunoblot, and proteomics-based expression analysis demonstrated that Ct-OATP1B3 protein is intracellularly localized in lysosomes of stably-transfetced cells. Cytotoxicity experiments showed that cells recombinantly expressing the Ct-OATP1B3 protein were more resistant against the kinase inhibitor encorafenib compared to control cells [e.g. encorafenib (100 µM) survival rates: 89.5% vs. 52.8%]. In line with these findings, colorectal cancer DLD1 cells endogenously expressing Ct-OATP1B3 protein had poorer survival rates when the OATP1B3 substrate bromosulfophthalein (BSP) was coincubated with encorafenib or vemurafenib compared to the incubation with the kinase inhibitor alone. This indicates a competitive inhibition of Ct-OATP1B3-mediated uptake into lysosomes by BSP. Accordingly, mass spectrometry-based drug analysis of lysosomes showed a reduced lysosomal accumulation of encorafenib in DLD1 cells additionally exposed to BSP. These results demonstrate that Ct-OATP1B3 protein is localized in the lysosomal membrane and can mediate transport of certain kinase inhibitors into lysosomes revealing a new mechanism of resistance.
Publisher: Wiley
Date: 29-06-2022
DOI: 10.1002/CPT.2682
Abstract: Green tea (GT) alters the disposition of a number of drugs, such as nadolol and lisinopril. However, it is unknown whether GT affects disposition of hydrophilic anti-allergic drugs. The purpose of this study was to investigate whether pharmacokinetics of fexofenadine and pseudoephedrine are affected by catechins, major GT components. A randomized, open, 2-phase crossover study was conducted in 10 healthy Japanese volunteers. After overnight fasting, subjects were simultaneously administered fexofenadine (60 mg) and pseudoephedrine (120 mg) with an aqueous solution of green tea extract (GTE) containing (-)-epigallocatechin gallate (EGCG) of ~ 300 mg or water (control). In vitro transport assays were performed using HEK293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated fexofenadine transport. In the GTE phase, the area under the plasma concentration-time curve and the amount excreted unchanged into urine for 24 hours of fexofenadine were significantly decreased by 70% (P < 0.001) and 67% (P < 0.001), respectively, compared with control. There were no differences in time to maximum plasma concentration and the elimination half-life of fexofenadine between phases. Fexofenadine was confirmed to be a substrate of OATP1A2, and EGCG (100 and 1,000 μM) and GTE (0.1 and 1 mg/mL) inhibited OATP1A2-mediated uptake of fexofenadine. On the contrary, the concomitant administration of GTE did not influence the pharmacokinetics of pseudoephedrine. These results suggest that intake of GT may result in a markedly reduced exposure of fexofenadine, but not of pseudoephedrine, putatively by inhibiting OATP1A2-mediated intestinal absorption.
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