Effects of pharmacological inhibition of the sodium‐dependent phosphate cotransporter 2b (NPT2b) on intestinal phosphate absorption in mouse and rat models

Pharmacology Research & Perspectives

Xiaohong Yu¹  Charity M. Zink¹  Derek Wodka¹  Joseph V. Haas¹  Hong Y. Zhang¹  William F. Matter¹  Xiaojun Wang¹  Jeffrey A. Peterson¹  Charles A. Reidy¹  Leah Porras¹  Mark C. Kowala¹  John R. Wetterau¹  Asim Dey¹  Brian E. Mattioni¹  Gina Porter¹  Yanping Xu¹ 

[1] Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana USA;

关键词: NPT2b;    Phosphate metabolism;   

DOI  :  10.1002/prp2.938

来源: DOAJ

【 摘 要 】

Abstract An excess phosphate burden in renal disease has pathological consequences for bone, kidney, and heart. Therapies to decrease intestinal phosphate absorption have been used to address the problem, but with limited success. Here, we describe the in vivo effects of a novel potent inhibitor of the intestinal sodium‐dependent phosphate cotransporter NPT2b, LY3358966. Following treatment with LY3358966, phosphate uptake into plasma 15 min following an oral dose of radiolabeled phosphate was decreased 74% and 22% in mice and rats, respectively, indicating NPT2b plays a much more dominant role in mice than rats. Following the treatment with LY3358966 and radiolabeled phosphate, mouse feces were collected for 48 h to determine the ability of LY3358966 to inhibit phosphate absorption. Compared to vehicle‐treated animals, there was a significant increase in radiolabeled phosphate recovered in feces (8.6% of the dose, p < .0001). Similar studies performed in rats also increased phosphate recovered in feces (5.3% of the dose, p < .05). When used in combination with the phosphate binder sevelamer in rats, there was a further small, but not significant, increase in fecal phosphate. In conclusion, LY3358966 revealed a more prominent role for NPT2b on acute intestinal phosphate uptake into plasma in mice than rats. However, the modest effects on total intestinal phosphate absorption observed in mice and rats with LY3359866 when used alone or in combination with sevelamer highlights the challenge to identify new more effective therapeutic targets and/or drug combinations to treat the phosphate burden in patients with renal disease.

【 授权许可】

Unknown