Universität zu Köln

Burckhardt, Birgitta C., Henjakovic, Maja, Hagos, Yohannes and Burckhardt, Gerhard (2016). Counter-flow suggests transport of dantrolene and 5-OH dantrolene by the organic anion transporters 2 (OAT2) and 3 (OAT3). Pflugers Arch., 468 (11-12). S. 1909 - 1919. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-2013

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Abstract

Dantrolene is the only available drug for the treatment of malignant hyperthermia, a life-threatening inborn sensitivity of the ryanodine receptor (RyR1) in skeletal muscles to volatile anesthetics. Dantrolene is metabolized in the liver to 5-OH dantrolene. Both compounds are zwitterions or net negatively charged. Here, we investigated interactions of dantrolene and 5-OH dantrolene with solute carrier (SLC) family members occurring in skeletal muscle cells, hepatocytes, and renal proximal tubule cells. SLC22A8 (organic anion transporter 3, OAT3) was very sensitive to both compounds exhibiting IC50 values of 0.35 +/- 0.03 and 1.84 +/- 0.34 mu M, respectively. These IC50 concentrations are well below the plasma concentration in patients treated with dantrolene (3-28 mu M). SLC22A7 (OAT2) was less sensitive to dantrolene and 5-OH dantrolene with IC50 values of 15.6 +/- 2.1 and 15.8 +/- 3.2 mu M, respectively. SLCO1B1 (OATP1B1), SLCO1B3 (OATP1B3), and SLCO2B1 (OATP2B1) mainly interacted with 5-OH dantrolene albeit with higher IC50 values than those observed for OAT2 and OAT3. Dantrolene and 5-OH dantrolene failed to inhibit uptake of 1-methyl-4-phenylpyrimidinium (MPP) by OCT1 and of carnitine by OCTN2. In counter-flow experiments on OAT3, dantrolene and 5-OH dantrolene decreased pre-equilibrated cellular [H-3]estrone-3-sulfate (ES) content as did the transported substrates glutarate, furosemide, and bumetanide. With OAT2, dantrolene and 5-OH dantrolene slightly decreased the pre-equilibrated [H-3] cGMP content. If no other transporter markedly contributes to uptake or release of ES or cGMP, respectively, these data suggest that OAT3 and OAT2 may be involved in absorption, metabolism, and excretion of dantrolene and its metabolite 5-OH dantrolene.

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:38-256533
DOI:	10.1007/s00424-016-1894-6
Journal or Publication Title:	Pflugers Arch.
Volume:	468
Number:	11-12
Page Range:	S. 1909 - 1919
Date:	2016
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-2013
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MALIGNANT HYPERTHERMIA; IDENTIFICATION; PHARMACOLOGY; INHIBITORS; EXPRESSION; SODIUM; GENES; DRUGS Multiple languages Physiology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25653