Töllner Kathrin, Brandt Claudia, Römermann Kerstin, Löscher Wolfgang
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
Eur J Pharmacol. 2015 Jan 5;746:167-73. doi: 10.1016/j.ejphar.2014.11.019. Epub 2014 Nov 20.
Bumetanide is increasingly being used for experimental treatment of brain disorders, including neonatal seizures, epilepsy, and autism, because the neuronal Na-K-Cl cotransporter NKCC1, which is inhibited by bumetanide, is implicated in the pathophysiology of such disorders. However, use of bumetanide for treatment of brain disorders is associated with problems, including poor brain penetration and systemic adverse effects such as diuresis, hypokalemic alkalosis, and hearing loss. The poor brain penetration is thought to be related to its high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, but more recently brain efflux transporters have been involved, too. Multidrug resistance protein 4 (MRP4), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 2 (OATP2) were suggested to mediate bumetanide brain efflux, but direct proof is lacking. Because MRP4, OAT3, and OATP2 can be inhibited by probenecid, we studied whether this drug alters brain levels of bumetanide in mice. Probenecid (50 mg/kg) significantly increased brain levels of bumetanide up to 3-fold; however, it also increased its plasma levels, so that the brain:plasma ratio (~0.015-0.02) was not altered. Probenecid markedly increased the plasma half-life of bumetanide, indicating reduced elimination of bumetanide most likely by inhibition of OAT-mediated transport of bumetanide in the kidney. However, the diuretic activity of bumetanide was not reduced by probenecid. In conclusion, our study demonstrates that the clinically available drug probenecid can be used to increase brain levels of bumetanide and decrease its elimination, which could have therapeutic potential in the treatment of brain disorders.
布美他尼越来越多地被用于脑部疾病的实验性治疗，包括新生儿惊厥、癫痫和自闭症，因为布美他尼所抑制的神经元钠-钾-氯协同转运蛋白NKCC1与这些疾病的病理生理学有关。然而，使用布美他尼治疗脑部疾病存在一些问题，包括脑内渗透性差以及诸如利尿、低钾性碱中毒和听力损失等全身不良反应。脑内渗透性差被认为与其高离子化率和血浆蛋白结合有关，这通过被动扩散限制了其进入脑内，但最近脑外排转运体也被牵涉其中。多药耐药蛋白4（MRP4）、有机阴离子转运体3（OAT3）和有机阴离子转运多肽2（OATP2）被认为介导布美他尼的脑外排，但缺乏直接证据。由于丙磺舒可以抑制MRP4、OAT3和OATP2，我们研究了这种药物是否会改变小鼠脑内布美他尼的水平。丙磺舒（50mg/kg）可使布美他尼的脑内水平显著升高至3倍；然而，它也会使其血浆水平升高，因此脑浆比（约0.015 - 0.02）未改变。丙磺舒显著延长了布美他尼的血浆半衰期，表明布美他尼的消除减少，最有可能是通过抑制OAT介导的布美他尼在肾脏中的转运。然而，丙磺舒并未降低布美他尼的利尿活性。总之，我们的研究表明，临床可用药物丙磺舒可用于提高布美他尼的脑内水平并减少其消除，这在脑部疾病的治疗中可能具有治疗潜力。
