In rats, tenapanor (0.15, 0.5 mg/kg; oral) decreases the absorption of passive paracellular phosphate [1]. Rats' decreased excretion of phosphorus in their urine is further reduced when given tenapanor (0.15 mg/kg; oral; twice daily for 11 days) [2].

Tenapanor inhibits paracellular phosphate flux in an intestinal epithelial cellular model
Intestinal epithelial stem cells from human or mouse gastrointestinal biopsies cultured as monolayers allow for monitoring of ion transport across the intestinal epithelium. The enteroid monolayer contains the diversity of intestinal epithelial cell lineages, models the specific gene expression patterns of each individual intestinal segment, expresses the appropriate endogenous ion transporters (for example, NHE3 and NaPi2b) in a segment-specific manner, polarizes to form tight junctions with segment-specific expression of claudins and other tight junction proteins, and generates the expected negative luminal electrical potential observed in vivo. The differentiated enteroid monolayer therefore enables the study of transcellular and paracellular phosphate absorption[1].

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Intestinal epithelial stem cell monolayer culture model[1].
Intestinal epithelial stem cell monolayers were cultured and differentiated on Transwells as described in detail by Kozuka et al.. Human biopsies from which stem cells were sourced were obtained from visibly healthy tissue from male donors according to a protocol approved by the Copernicus Group Institutional Review Board. Experiments were initiated in each differentiated monolayer culture well by washing the apical and basolateral side twice with fresh supplemented basal media and phosphate-free Dulbecco’s modified Eagle’s medium. Compounds were dosed only on the apical side of the monolayer, as detailed in the text; DMSO at an equivalent concentration was used as the control. Phosphate concentration and pH were manipulated as described in the text. Apical and basolateral ion concentrations were measured by ion chromatography, pH was measured using a pH meter, and TEER values were recorded using a volt/ohm meter. TEER results are reported as normalized to baseline. Absolute baseline TEER values are reported in table S1.

Animal/Disease Models: Rats (intestinal loop model)[1]
Doses: 0.15, 0.5 mg/kg
Route of Administration: Po
Experimental Results: decreased passive paracellular phosphate absorption by decreased urinary phosphate and sodium excretion after the high-phosphate meal and increased sodium and phosphate delivery to the cecum.

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Animal/Disease Models: 8 weeks, 250 g male Sprague–Dawley rats[2]
Doses: 0.15 mg/kg in combination with sevelamer (0%, 0.75%, 1.5%, and 3% (wt/wt))
Route of Administration: po (oral gavage); twice-daily for 11 days
Experimental Results: Dramatically augmented the reduction in urinary phosphorus excretion.

Absorption, Distribution and Excretion
Tenapanor undergoes very minimal systemic absorption following oral administration. During clinical trials, plasma concentrations were below the limit of quantitation (i.e. less than 0.5 ng/mL) in the majority of samples from healthy subjects - for this reason, typical pharmacokinetic values related to absorption such as AUC and Cmax were unable to be ascertained. The effects of tenapanor are greatest when administered 5 to 10 minutes before meals.
Following administration of a radio labeled dose of tenapanor, 70% of the radioactivity was excreted in the feces within 120 hours of administration and 79% within 240 hours. Approximately 65% of the total dose is excreted as unchanged parent drug within 144 hours of administration. Only 9% of the administered dose was found in the urine, existing primarily as metabolites. Tenapanor's M1 metabolite is excreted unchanged in the urine and accounts for approximately 1.5% of the total dose within 144 hours of administration.

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Metabolism / Metabolites
The majority of tenapanor's metabolism to its primary metabolite, M1, is catalyzed via CYP3A4/5. Exposure of tenapanor to hepatic CYP enzymes is likely limited due to its minimal systemic absorption, so its metabolism may be due to intestinal CYP enzyme activity. The M1 metabolite of tenapanor is a P-glycoprotein substrate and, in contrast to its parent drug, can be detected in plasma, reaching a C_max of approximately 15 ng/mL at steady state. It is not considered active against NHE3.

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Biological Half-Life
Tenapanor's FDA label states that its half-life could not be determined during clinical trials due to its minimal systemic absorption resulting in plasma concentrations below the limit of quantitation (i.e. less than 0.5 ng/mL).

Hepatotoxicity
When given orally, tenapanor has minimal systemic absorption and has not been associated with elevations in serum enzymes or bilirubin or with instances of clinically apparent liver injury. Since approval and general availability of tenapanor, there have been no published reports of liver injury attributed to its use.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Tenapanor is essentially non-absorbed systemically, with undetectable plasma concentrations following oral administration. The minimal systemic absorption of tenapanor will not result in a clinically relevant exposure to breastfed infants. No special precautions are necessary.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Both tenapanor and its principle metabolite, M1, are highly plasma protein bound at approximately 99% and 97%, respectively. The specific proteins to which tenapanor and its metabolite binds have yet to be elucidated.

[1]. Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med. 2018 Aug 29;10(456):eaam6474.

[2]. Combination treatment with tenapanor and sevelamer synergistically reduces urinary phosphorus excretion in rats. Am J Physiol Renal Physiol. 2021 Jan 1;320(1):F133-F144.

Tenapanor is a novel, small molecule medication approved in September 2019 for the treatment of constipation-predominant irritable bowel-syndrome (IBS-C). It was first designed and synthesized in 2012. As an inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3) transporter, it is the first and currently only medication within its class and therefore exists as a novel alternative in the treatment of IBS-C. In October 2023, tenapanor was approved for the treatment of chronic kidney disease.
Tenapanor is a Sodium-Hydrogen Exchanger 3 Inhibitor. The mechanism of action of tenapanor is as a Sodium-Hydrogen Exchanger 3 Inhibitor, and Organic Anion Transporting Polypeptide 2B1 Inhibitor.
Tenapanor is a small molecular inhibitor of the sodium/hydrogen ion exchanger-3 (NHE3) used to treat constipation predominant irritable bowel syndrome (IBS). Tenapanor has minimal systemic absorption and has not been associated with serum enzyme elevation during therapy nor has it been linked to cases of clinically apparent liver injury.
See also: Tenapanor Hydrochloride (active moiety of).

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Drug Indication
Tenapanor is indicated for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in adults. It is also indicated to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis as add-on therapy in patients who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binder therapy.

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Mechanism of Action
Tenapanor is a locally-acting small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), an antiporter expressed on the apical surface of enterocytes in the small intestine and colon which is involved in sodium-fluid homeostasis. By inhibiting this antiporter tenapanor causes retention of sodium within the lumen of the intestine - this results in an osmotic gradient that draws water into the lumen and softens stool consistency. There is some evidence that tenapanor can inhibit the uptake of dietary phosphorus in the gastrointestinal tract, though the exact mechanism of this activity has yet to be elucidated.

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Pharmacodynamics
Through the inhibition of dietary sodium absorption tenapanor causes an increase in water secretion into the intestines, thereby decreasing transit time and softening stool consistency.

C50H66CL4N8O10S2

1145.0486

1142.309

C, 52.45; H, 5.81; Cl, 12.38; N, 9.79; O, 13.97; S, 5.60

1234423-95-0

Tenapanor hydrochloride;1234365-97-9

71587953

Typically exists as white to off-white solids at room temperature

1.3±0.1 g/cm3

1.590

4.85

6

14

29

74

1770

2

ClC1=C([H])C(=C([H])C2=C1C([H])([H])N(C([H])([H])[H])C([H])([H])[C@@]2([H])C1C([H])=C([H])C([H])=C(C=1[H])S(N([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])N([H])C(N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(N([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])N([H])S(C1=C([H])C([H])=C([H])C(=C1[H])[C@@]1([H])C2C([H])=C(C([H])=C(C=2C([H])([H])N(C([H])([H])[H])C1([H])[H])Cl)Cl)(=O)=O)=O)=O)(=O)=O)Cl

DNHPDWGIXIMXSA-CXNSMIOJSA-N

InChI=1S/C50H66Cl4N8O10S2/c1-61-31-43(41-27-37(51)29-47(53)45(41)33-61)35-7-5-9-39(25-35)73(65,66)59-15-19-71-23-21-69-17-13-57-49(63)55-11-3-4-12-56-50(64)58-14-18-70-22-24-72-20-16-60-74(67,68)40-10-6-8-36(26-40)44-32-62(2)34-46-42(44)28-38(52)30-48(46)54/h5-10,25-30,43-44,59-60H,3-4,11-24,31-34H2,1-2H3,(H2,55,57,63)(H2,56,58,64)/t43-,44-/m0/s1

3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-((3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl)benzenesulfonamide

RDX 5791; AZD 1722; RDX-5791; AZD1722; RDX5791; AZD-1722; Tenapanor free base;Tenapanor; 1234423-95-0; KHK7791; KHK-7791;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~43.67 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.18 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (2.18 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (2.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 2.5 mg/mL (2.18 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)