%0 Journal Article %1 fu2018organic %A Fu, Y. %A Breljak, D. %A Onishi, A. %A Batz, F. %A Patel, R. %A Huang, W. %A Song, P. %A Freeman, B. %A Mayoux, E. %A Koepsell, H. %A Anzai, N. %A Nigam, S. K. %A Sabolic, I. %A Vallon, V. %D 2018 %J Am J Physiol Renal Physiol %K Animals myOwn %N 2 %P F386-F394 %R 10.1152/ajprenal.00503.2017 %T Organic anion transporter OAT3 enhances the glucosuric effect of the SGLT2 inhibitor empagliflozin %U https://www.ncbi.nlm.nih.gov/pubmed/29412698 %V 315 %X The sodium-glucose cotransporter SGLT2 inhibitor empagliflozin (plasma protein binding ~88%) may reach its target in the brush border of the early proximal tubule by glomerular filtration and tubular secretion. Here we determined whether empagliflozin is secreted by renal tubules in mice and whether genetic knockout of the basolateral organic anion transporter 3 ( Oat3-/-) affects its tubular secretion or glucosuric effect. Renal clearance studies in wild-type (WT) mice showed that tubular secretion accounted for 50-70% of empagliflozin urinary excretion. Immunostaining indicated that SGLT2 and OAT3 localization partially overlapped in proximal tubule S1 and S2 segments. Glucosuria in metabolic cage studies was reduced in Oat3-/- vs. WT mice for acute empagliflozin doses of 1, 3, and 10 mg/kg, whereas 30 mg/kg induced similar maximal glucosuria in both genotypes. Chronic application of empagliflozin (~25 mg.kg(-1) .day(-1)) in Oat3-/- mice was associated with lower urinary glucose-to-creatinine ratios despite maintaining slightly higher blood glucose levels than WT. On a whole kidney level, renal secretion of empagliflozin was largely unchanged in Oat3-/- mice. However, the absence of OAT3 attenuated the influence of empagliflozin on fractional glucose excretion; higher levels of plasma or filtered empagliflozin were needed to induce similar increases in fractional renal glucose excretion. We conclude that empagliflozin is excreted into the urine to similar extent by glomerular filtration and tubular secretion. The latter can occur largely independent of OAT3. However, OAT3 increases the glucosuric effect of empagliflozin, which may relate to the partial overlap of its localization with SGLT2 and thus OAT3-mediated tubular secretion of empagliflozin in the early proximal tubule.

@article{fu2018organic, abstract = {The sodium-glucose cotransporter SGLT2 inhibitor empagliflozin (plasma protein binding ~88%) may reach its target in the brush border of the early proximal tubule by glomerular filtration and tubular secretion. Here we determined whether empagliflozin is secreted by renal tubules in mice and whether genetic knockout of the basolateral organic anion transporter 3 ( Oat3-/-) affects its tubular secretion or glucosuric effect. Renal clearance studies in wild-type (WT) mice showed that tubular secretion accounted for 50-70% of empagliflozin urinary excretion. Immunostaining indicated that SGLT2 and OAT3 localization partially overlapped in proximal tubule S1 and S2 segments. Glucosuria in metabolic cage studies was reduced in Oat3-/- vs. WT mice for acute empagliflozin doses of 1, 3, and 10 mg/kg, whereas 30 mg/kg induced similar maximal glucosuria in both genotypes. Chronic application of empagliflozin (~25 mg.kg(-1) .day(-1)) in Oat3-/- mice was associated with lower urinary glucose-to-creatinine ratios despite maintaining slightly higher blood glucose levels than WT. On a whole kidney level, renal secretion of empagliflozin was largely unchanged in Oat3-/- mice. However, the absence of OAT3 attenuated the influence of empagliflozin on fractional glucose excretion; higher levels of plasma or filtered empagliflozin were needed to induce similar increases in fractional renal glucose excretion. We conclude that empagliflozin is excreted into the urine to similar extent by glomerular filtration and tubular secretion. The latter can occur largely independent of OAT3. However, OAT3 increases the glucosuric effect of empagliflozin, which may relate to the partial overlap of its localization with SGLT2 and thus OAT3-mediated tubular secretion of empagliflozin in the early proximal tubule.}, added-at = {2024-02-15T15:08:22.000+0100}, author = {Fu, Y. and Breljak, D. and Onishi, A. and Batz, F. and Patel, R. and Huang, W. and Song, P. and Freeman, B. and Mayoux, E. and Koepsell, H. and Anzai, N. and Nigam, S. K. and Sabolic, I. and Vallon, V.}, biburl = {https://www.bibsonomy.org/bibtex/20a13ebc334f5d4ea92f6e15a9be76426/jvsi_all}, doi = {10.1152/ajprenal.00503.2017}, interhash = {1a4e58835bd86d1c6f0695f6a7b2ed7e}, intrahash = {0a13ebc334f5d4ea92f6e15a9be76426}, issn = {1522-1466 (Electronic) 1931-857X (Print) 1522-1466 (Linking)}, journal = {Am J Physiol Renal Physiol}, keywords = {Animals myOwn}, note = {Fu, Yiling Breljak, Davorka Onishi, Akira Batz, Falk Patel, Rohit Huang, Winnie Song, Panai Freeman, Brent Mayoux, Eric Koepsell, Hermann Anzai, Naohiko Nigam, Sanjay K Sabolic, Ivan Vallon, Volker eng P30 DK079337/DK/NIDDK NIH HHS/ R01 DK109392/DK/NIDDK NIH HHS/ R01 DK106102/DK/NIDDK NIH HHS/ R01 DK112042/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2018/02/08 Am J Physiol Renal Physiol. 2018 Aug 1;315(2):F386-F394. doi: 10.1152/ajprenal.00503.2017. Epub 2018 Feb 7.}, number = 2, pages = {F386-F394}, timestamp = {2024-02-15T15:08:22.000+0100}, title = {Organic anion transporter OAT3 enhances the glucosuric effect of the SGLT2 inhibitor empagliflozin}, type = {Journal Article}, url = {https://www.ncbi.nlm.nih.gov/pubmed/29412698}, volume = 315, year = 2018 }