Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences (R.S.J., D.R., M.E.M.) and Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences (M.D.P.), University at Buffalo, State University of New York, Buffalo, New York.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences (R.S.J., D.R., M.E.M.) and Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences (M.D.P.), University at Buffalo, State University of New York, Buffalo, New York
Drug Metab Dispos. 2020 Sep;48(9):788-795. doi: 10.1124/dmd.120.000068. Epub 2020 Jun 25.
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 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.
布美他尼是一种磺酰脲类袢利尿剂，用于治疗充血性心力衰竭相关的水肿。作为一种在生理 pH 下为极性、阴离子化合物，布美他尼在不同组织中的摄取和外排在很大程度上是由转运体介导的。值得注意的是，有机阴离子转运体（SLC22A）在将布美他尼转运到其在肾脏中的主要作用部位方面已得到广泛研究。较少研究的布美他尼转运体之一，单羧酸转运体 6（MCT6；SLC16A5）对布美他尼药代动力学（PK）和药效动力学（PD）的贡献尚未确定。布美他尼对鼠 Mct6 的亲和力使用 Mct6 转染的卵母细胞进行了评估。此外，将布美他尼静脉内和口服给予野生型小鼠（Mct6）和纯合 Mct6 敲除小鼠（Mct6），以阐明 Mct6 对体内布美他尼 PK/PD 的贡献。我们证明，与人类 MCT6 相比，鼠 Mct6 以相似的亲和力转运布美他尼（分别在 pH7.4 时为 78 和 84 μM）。给予布美他尼后，血浆 PK 无显著差异。此外，静脉内给予布美他尼后，Mct6 小鼠的尿量减少约 55%。布美他尼在肾脏皮质中的浓度降低，表明 Mct6 介导的布美他尼向肾脏作用部位的转运减少。总的来说，这些结果表明，Mct6 在小鼠中对布美他尼的血浆 PK 没有重要作用；然而，由于肾脏浓度的变化，它对布美他尼的药效学有显著贡献。意义声明：先前的证据表明 MCT6 在体外转运布美他尼；然而，迄今为止尚无研究评估该转运体的体内作用。体外研究表明，鼠和人 MCT6 以相似的亲和力转运布美他尼。使用 Mct6 敲除小鼠，我们证明鼠 Mct6 在布美他尼的血浆药代动力学中没有重要作用；然而，在敲除小鼠中利尿作用减弱，可能是因为肾脏中布美他尼浓度降低。
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