Abstract: TH-PO1047

A Novel, Selective, and Non-Systemic Na+/H+ Exchanger 3 Inhibitor, TP0469711, Potently Enhances Phosphate Excretion with a Favorable Gastrointestinal Tolerability in Rats

Session Information

Category: Mineral Disease

  • 1201 Mineral Disease: Ca/Mg/PO4

Authors

  • Munetomo, Eiji, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
  • Takahashi, Teisuke, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
  • Yamamoto, Koji, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
  • Abe, Tomohiro, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
  • Tomoike, Hideki, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
  • Kajiyama, Hiromitsu, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
  • Koyasu, Saori, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
  • Okumura, Lisa, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
  • Kuroda, Shoichi, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
  • Mori, Haruyuki, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
  • Ushiki, Yasunobu, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
Background

Na+/H+ Exchanger 3 (NHE3) inhibitor is known to enhance the excretion of phosphate and expected as a new candidate for anti-hyperphosphatemia drug. However, NHE3 inhibitor also causes diarrhea frequently because of the excessive enhancement of Na excretion.

Methods

NHE1, NHE2 and NHE3 activities of TP0469711 (TP) were evaluated by measuring intracellular pH recovery in each NHE over-expressing cells. Na-dependent phosphate transporter 2b (NaPi2b) activity was evaluated by uptake of 33P phosphate in NaPi2b over-expressing cells. To examine the effect of TP on the phosphate absorption and excretion, the radioactivity of 32P phosphate in the blood and feces were measured after oral administration of TP. Inhibitory effects of NHE3 by TP were evaluated by measuring pH and luminal Na content in the intestinal tract. Na excretion and water content in feces up to 24 hours were evaluated after oral dosing of TP in rats.

Results

TP inhibited human and rat NHE3 activities with IC50 values of 2.2 and 2.1 nM, respectively. However, TP (3 μM) had no effects on human NHE1, NHE2 and NaPi2b activities. Oral administration of TP increased pH of luminal content in the upper intestine in a dose-dependent manner in rats. TP (0.1 mg/kg, p.o.) significantly decreased the area under the curve of plasma 32P phosphate radioactivity by 40.7 ± 4.7 % (n=5, P < 0.001). TP (0.1 mg/kg, p.o.) significantly increased the fecal excretion of phosphate by 62 % (n=6, P < 0.05), without affecting Na excretion and water content in feces. TP significantly enhanced the excretion of Na and increased water content at a higher dose of 1 mg/kg (n=7, P < 0.01). Over dose of TP (30 mg/kg, p.o.) did not raise plasma concentration (< 1 ng/ml), which means TP is a non-systemic NHE3 inhibitor.

Conclusion

We discovered a novel, selective and non-systemic NHE3 inhibitor, TP0469711, which potently excreted phosphate into feces with a favorable gastrointestinal tolerability in rats. TP is suitable for a new therapeutic agent for the treatment of hyperphosphatemia in patients with end-stage renal disease.

Funding

  • Commercial Support