Tenapanor is an inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3, which plays a prominent role in sodium handling in the gastrointestinal tract and kidney, with IC50 values of 5 and 10 nM against human and rat NHE3, respectively.
The management of sodium intake is clinically important in many disease states including heart failure, kidney disease, and hypertension. NHE3 (sodium-proton (Na+/H+) exchanger 3) makes the major contribution to intestinal sodium uptake. Tenapanor is a NHE3 inhibitor with IC50 values of 5 and 10 nM against human and Rat NHE3, respectively. Upon administering single doses of tenapanor to rats, there were dose-dependent reductions in urinary sodium and increases in fecal sodium and luminal fluid mass, and these values were associated with increasing tenapanor concentration in the intestinal lumen. Stool form score increased with tenapanor dose from a baseline of 1.2 to 2.2 (0.3 mg/kg), 3.3 (1 mg/kg), and 4.5 (3 mg/kg). Further, the acute negative sodium balance observed in the absence of exogenous sodium diminished during prolonged feeding of a sodium-free diet with tenapanor administration. Furthermore, chronic administration of tenapanor to rats fed with standard chow (0.49% NaCl) caused a sustained reduction of urinary sodium and increase in fecal sodium, both of which normalized upon tenapanor withdrawal. Repeated administration of tenapanor at 1, 3, or 10 mg/kg per day increased day 3 to 4 plasma aldosterone concentrations. These data from normal rats support a mechanism of action in which tenapanor acts to reduce intestinal sodium uptake. In healthy human subjects, administration of 15 to 60 mg of tenapanor twice daily produced an increase in fecal sodium of 20 to 50 mmol/day and decreases of similar magnitude in urinary sodium[1].
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