RT Journal Article
SR Electronic
T1 Contribution of monocarboxylate transporter 6 (Mct6) to the pharmacokinetics and pharmacodynamics of bumetanide in mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2020-000068
DO 10.1124/dmd.120.000068
A1 Robert S. Jones
A1 Donna Ruszaj
A1 Mark D. Parker
A1 Marilyn E. Morris
YR 2020
UL http://dmd.aspetjournals.org/content/early/2020/06/25/dmd.120.000068.abstract
AB Bumetanide, a sulfamyl loop diuretic, is used for the treatment of edema in association with congestive heart failure. Being a polar, anionic compound at physiological pH, bumetanide uptake and efflux into different tissues is largely transporter-mediated. Of note, organic anion transporters (OAT; SLC22A) have been extensively studied in terms of their importance in transporting bumetanide to its primary site of action in the kidney. The contribution of one of the less-studied bumetanide transporters, monocarboxylate transporter 6 (MCT6; SLC16A5), to bumetanide pharmacokinetics (PK) and pharmacodynamics (PD) has yet to be characterized. The affinity of bumetanide for murine Mct6 was evaluated using Mct6-transfected Xenopus laevis oocytes. Furthermore, bumetanide was intravenously and orally administered to wildtype mice (Mct6+/+) and homozygous Mct6 knockout mice (Mct6-/-) to elucidate the contribution of Mct6 to bumetanide PK/PD in vivo. We demonstrated that murine Mct6 transports bumetanide at a similar affinity compared with human MCT6 (78 and 84 μM, respectively, at pH 7.4). Following bumetanide administration, there were no significant differences in plasma PK. Additionally, diuresis was significantly decreased by ~55% after intravenous bumetanide administration in Mct6-/- mice. Kidney cortex concentrations of bumetanide were decreased, suggesting decreased Mct6-mediated bumetanide transport to its site of action in the kidney. Overall, these results suggest that Mct6 does not play a major role in the plasma PK of bumetanide in mice; however, it significantly contributes to bumetanide's pharmacodynamics due to changes in kidney concentrations.