Counter-flow suggests transport of dantrolene and 5-OH dantrolene by the organic anion transporters 2 (OAT2) and 3 (OAT3).
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 IC50values of 0.35 ± 0.03 and 1.84 ± 0.34 μM, respectively. These IC50concentrations are well below the plasma concentration in patients treated with dantrolene (3-28 μM). SLC22A7 (OAT2) was less sensitive to dantrolene and 5-OH dantrolene with IC50values of 15.6 ± 2.1 and 15.8 ± 3.2 μM, respectively. SLCO1B1 (OATP1B1), SLCO1B3 (OATP1B3), and SLCO2B1 (OATP2B1) mainly interacted with 5-OH dantrolene albeit with higher IC50values 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 [3H]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 [3H]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.
Institute of Systemic Physiology and Pathophysiology, University Medical Center Göttingen, Humboldtallee 23, 37073, Göttingen, Germany. birgitta.burckhardt@med.uni-goettingen.de.
Birgitta C
BC
Burckhardt
Institute of Systemic Physiology and Pathophysiology, University Medical Center Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.|Department of Internal Medicine, University Medical Center Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
Maja
M
Henjakovic
Institute of Systemic Physiology and Pathophysiology, University Medical Center Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.|PortaCellTec Biosciences GmbH, Humboldtallee 23, 37073, Göttingen, Germany.
Yohannes
Y
Hagos
Institute of Systemic Physiology and Pathophysiology, University Medical Center Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.
Gerhard
G
Burckhardt
D001692:Biological Transport; D003620:Dantrolene / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D011485:Protein Binding
D009125:Muscle Relaxants, Central; D029362:Organic Anion Transporters, Sodium-Independent; C490280:SLC22A7 protein, human; C114338:organic anion transport protein 3; D003620:Dantrolene