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Drug Metab Dispos
2020 Sep 01;489:788-795. doi: 10.1124/dmd.120.000068.
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Contribution of Monocarboxylate Transporter 6 to the Pharmacokinetics and Pharmacodynamics of Bumetanide in Mice.
Jones RS
,
Ruszaj D
,
Parker MD
,
Morris ME
.
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Bumetanide, a sulfamyl loop diuretic, is used for the treatment of edema in association with congestive heart failure. Being a polar, anionic compound at physiologic pH, bumetanide uptake and efflux into different tissues is largely transporter-mediated. Of note, organic anion transporters (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 wild-type 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). After 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. SIGNIFICANCE STATEMENT: Previous evidence suggested that MCT6 transports bumetanide in vitro; however, no studies to date have evaluated the in vivo contribution of this transporter. In vitro studies indicated that mouse and human MCT6 transport bumetanide with similar affinities. Using Mct6 knockout mice, we demonstrated that murine Mct6 does not play a major role in the plasma pharmacokinetics of bumetanide; however, the pharmacodynamic effect of diuresis was attenuated in the knockout mice, likely because of the decreased bumetanide concentrations in the kidney.
Blaesse,
Cation-chloride cotransporters and neuronal function.
2009, Pubmed
Blaesse,
Cation-chloride cotransporters and neuronal function.
2009,
Pubmed
Brandt,
Disease-modifying effects of phenobarbital and the NKCC1 inhibitor bumetanide in the pilocarpine model of temporal lobe epilepsy.
2010,
Pubmed
Brater,
Bumetanide and furosemide in heart failure.
1984,
Pubmed
Cleary,
Bumetanide enhances phenobarbital efficacy in a rat model of hypoxic neonatal seizures.
2013,
Pubmed
Cook,
Kinetics, dynamics, and bioavailability of bumetanide in healthy subjects and patients with congestive heart failure.
1988,
Pubmed
Dixon,
Bumetanide: radioimmunoassay and pharmacokinetic profile in humans.
1976,
Pubmed
Gill,
Expression and membrane localization of MCT isoforms along the length of the human intestine.
2005,
Pubmed
Haas,
The Na-K-Cl cotransporters.
1998,
Pubmed
Han,
Pharmacokinetics and pharmacodynamics of bumetanide after intravenous and oral administration to spontaneously hypertensive rats and DOCA-salt induced hypertensive rats.
1993,
Pubmed
Hasannejad,
Interactions of human organic anion transporters with diuretics.
2004,
Pubmed
Holazo,
Pharmacokinetics of bumetanide following intravenous, intramuscular, and oral administrations to normal subjects.
1984,
Pubmed
Jones,
Quercetin, Morin, Luteolin, and Phloretin Are Dietary Flavonoid Inhibitors of Monocarboxylate Transporter 6.
2017,
Pubmed
,
Xenbase
Jones,
Monocarboxylate Transporter 6-Mediated Interactions with Prostaglandin F2α: In Vitro and In Vivo Evidence Utilizing a Knockout Mouse Model.
2020,
Pubmed
Jones,
Characterization and Proteomic-Transcriptomic Investigation of Monocarboxylate Transporter 6 Knockout Mice: Evidence of a Potential Role in Glucose and Lipid Metabolism.
2019,
Pubmed
,
Xenbase
Kahle,
Decreased seizure activity in a human neonate treated with bumetanide, an inhibitor of the Na(+)-K(+)-2Cl(-) cotransporter NKCC1.
2009,
Pubmed
Kim,
Pharmacokinetics and pharmacodynamics of intravenous bumetanide in mutant Nagase analbuminemic rats: importance of globulin binding for the pharmacodynamic effects.
2001,
Pubmed
Kobayashi,
Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]).
2005,
Pubmed
,
Xenbase
Kohyama,
Characterization of monocarboxylate transporter 6: expression in human intestine and transport of the antidiabetic drug nateglinide.
2013,
Pubmed
,
Xenbase
Lee,
Pharmacokinetics and pharmacodynamics of bumetanide after intravenous and oral administration to rats: absorption from various GI segments.
1994,
Pubmed
Levine,
Modulation of single-nephron GFR in the db/db mouse model of type 2 diabetes mellitus.
2006,
Pubmed
Lytle,
Distribution and diversity of Na-K-Cl cotransport proteins: a study with monoclonal antibodies.
1995,
Pubmed
,
Xenbase
Mao,
Molecular and functional expression of cation-chloride cotransporters in dorsal root ganglion neurons during postnatal maturation.
2012,
Pubmed
Murakami,
Functional characterization of human monocarboxylate transporter 6 (SLC16A5).
2005,
Pubmed
,
Xenbase
Musa-Aziz,
Using fluorometry and ion-sensitive microelectrodes to study the functional expression of heterologously-expressed ion channels and transporters in Xenopus oocytes.
2010,
Pubmed
,
Xenbase
Pentikäinen,
Fate of [14C]-bumetanide in man.
1977,
Pubmed
Puskarjov,
Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures.
2014,
Pubmed
Römermann,
Multiple blood-brain barrier transport mechanisms limit bumetanide accumulation, and therapeutic potential, in the mammalian brain.
2017,
Pubmed
Smith,
Determinants of bumetanide response in the dog: effect of probenecid.
1983,
Pubmed
Töllner,
The organic anion transport inhibitor probenecid increases brain concentrations of the NKCC1 inhibitor bumetanide.
2015,
Pubmed
Töpfer,
Consequences of inhibition of bumetanide metabolism in rodents on brain penetration and effects of bumetanide in chronic models of epilepsy.
2014,
Pubmed
Weaver,
Pharmacokinetics and metabolism of nateglinide in humans.
2001,
Pubmed
Xu,
Impairment of Intestinal Monocarboxylate Transporter 6 Function and Expression in Diabetic Rats Induced by Combination of High-Fat Diet and Low Dose of Streptozocin: Involvement of Butyrate-Peroxisome Proliferator-Activated Receptor-γ Activation.
2019,
Pubmed