Universität zu Köln

Burckhardt, Birgitta C., Henjakovic, Maja, Hagos, Yohannes and Burckhardt, Gerhard (2017). Differential Interaction of Dantrolene, Glafenine, Nalidixic Acid, and Prazosin with Human Organic Anion Transporters 1 and 3. J. Pharmacol. Exp. Ther., 362 (3). S. 450 - 459. BETHESDA: AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS. ISSN 1521-0103

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Abstract

In renal proximal tubule cells, the organic anion transporters 1 and 3 (OAT1 and OAT3) in the basolateral membrane and the multidrug resistance-associated protein 4 (MRP4) in the apical membrane share substrates and co-operate in renal drug secretion. We hypothesized that recently identified MRP4 inhibitors dantrolene, glafenine, nalidixic acid, and prazosin also interact with human OAT1 and/or OAT3 stably transfected in human embryonic kidney 293 cells. These four drugs were tested as possible inhibitors of p-[H-3] aminohippurate (PAH) and [C-14] glutarate uptake by OAT1, and of [H-3]estrone-3-sulfate (ES) uptake by OAT3. In addition, we explored whether these drugs decrease the equilibrium distribution of radiolabeled PAH, glutarate, or ES, an approach intended to indirectly suggest drug/substrate exchange through OAT1 and OAT3. With OAT3, a dose-dependent inhibition of [H-3]ES uptake and a downward shift in [H-3] ES equilibrium were observed, indicating that all four drugs bind to OAT3 and may possibly be translocated. In contrast, the interaction with OAT1 was more complex. With [C-14] glutarate as substrate, all four drugs inhibited uptake but only glafenine and nalidixic acid shifted glutarate equilibrium. Using [H-3] PAH as a substrate of OAT1, nalidixic acid inhibited but dantrolene, glafenine, and prazosin stimulated uptake. Nalidixic acid decreased equilibrium content of [H-3] PAH, suggesting that itmay possibly be exchanged by OAT1. Taken together, OAT1 and OAT3 interact with the MRP4 inhibitors dantrolene, glafenine, nalidixic acid, and prazosin, indicating overlapping specificities. At OAT1, more than one binding site must be assumed to explain substrate and drug- dependent stimulation and inhibition of transport activity.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Burckhardt, Birgitta C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Henjakovic, Maja UNSPECIFIED UNSPECIFIED UNSPECIFIED Hagos, Yohannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Burckhardt, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-220475
DOI:	10.1124/jpet.117.241406
Journal or Publication Title:	J. Pharmacol. Exp. Ther.
Volume:	362
Number:	3
Page Range:	S. 450 - 459
Date:	2017
Publisher:	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
Place of Publication:	BETHESDA
ISSN:	1521-0103
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CATION TRANSPORTER; MULTIPLE MECHANISMS; HEALTHY-VOLUNTEERS; DRUGS; RESISTANCE; BINDING; MRP4; PHARMACOKINETICS; IDENTIFICATION; PHARMACOLOGY Multiple languages Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22047