Identification
- Summary
Tenapanor is an NHE3 inhibitor indicated for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic kidney disease,
- Brand Names
- Ibsrela, Xphozah
- Generic Name
- Tenapanor
- DrugBank Accession Number
- DB11761
- Background
Tenapanor is a novel, small molecule medication approved in September 2019 for the treatment of constipation-predominant irritable bowel-syndrome (IBS-C).6 It was first designed and synthesized in 2012.2 As an inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3) transporter, it is the first and currently only medication within its class1,2,3 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.7
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Tenapanor (DB11761)
- Weight
- Average: 1145.04
Monoisotopic: 1142.3097435 - Chemical Formula
- C50H66Cl4N8O10S2
- Synonyms
- Tenapanor
- External IDs
- AZD-1722
Pharmacology
- Indication
Tenapanor is indicated for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in adults.6
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.7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Adjunct therapy in treatment of Chronic kidney disease (ckd) •••••••••••• ••••• •••••••••• •••••••• •• •• ••••••••••• •• ••••••••• ••••••• •••••• Treatment of Irritable bowel syndrome with constipation (ibs-c) •••••••••••• ••••• •••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- 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.6
- 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.6,2,3
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.5
Target Actions Organism ASodium/hydrogen exchanger 3 inhibitorHumans - Absorption
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.6,3
The effects of tenapanor are greatest when administered 5 to 10 minutes before meals.6,3
- Volume of distribution
Not Available
- 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.6
- Metabolism
The majority of tenapanor's metabolism to its primary metabolite, M1, is catalyzed via CYP3A4/5.6 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.1
The M1 metabolite of tenapanor is a P-glycoprotein substrate and, in contrast to its parent drug, can be detected in plasma, reaching a Cmax of approximately 15 ng/mL at steady state.6 It is not considered active against NHE3.
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- Route of elimination
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.6
- 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).6
- Clearance
Not Available
- Adverse Effects
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Symptoms of overdose are likely to be consistent with tenapanor's adverse effect profile, and may therefore include gastrointestinal effects such as diarrhea. Dehydration may occur depending on duration and severity of diarrhea.6 No specific management strategies have been proposed in cases of overdose.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAsunaprevir The serum concentration of Asunaprevir can be decreased when it is combined with Tenapanor. Atorvastatin The serum concentration of Atorvastatin can be decreased when it is combined with Tenapanor. Fexofenadine The serum concentration of Fexofenadine can be decreased when it is combined with Tenapanor. Mesalazine The serum concentration of Mesalazine can be decreased when it is combined with Tenapanor. Pitavastatin The serum concentration of Pitavastatin can be decreased when it is combined with Tenapanor. - Food Interactions
- Take before a meal. Tenapanor should be administered immediately prior to the first meal of the day and immediately prior to dinner.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Tenapanor hydrochloride 50605O2ZNS 1234365-97-9 VFRAXTZDILCRKY-OWRGXFNZSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ibsrela Tablet 50 mg Oral Knight Therapeutics Inc. 2020-11-23 Not applicable Canada 
Ibsrela Tablet 53.2 mg/1 Oral Ardelyx, Inc. 2019-09-12 Not applicable US 
XPHOZAH 10 mg Tablet, film coated 10.6 mg/1 Oral Ardelyx, Inc. 2023-10-17 Not applicable US XPHOZAH 20 mg Tablet, film coated 21.3 mg/1 Oral Ardelyx, Inc. 2023-10-17 Not applicable US XPHOZAH 30 mg Tablet, film coated 31.9 mg/1 Oral Ardelyx, Inc. 2023-10-17 Not applicable US
Categories
- ATC Codes
- A06AX08 — Tenapanor
- Drug Categories
- Alimentary Tract and Metabolism
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Substrates
- Drugs for Constipation
- Heterocyclic Compounds, Fused-Ring
- Organic Anion Transporting Polypeptide 2B1 Inhibitors
- Sodium-Hydrogen Exchanger 3 Inhibitor
- Sodium/Hydrogen Exchanger 3 (NHE3) Inhibitors
- Sulfur Compounds
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as 4-phenyltetrahydroisoquinolines. These are compounds containing a phenyl group attached to the C4-atom of a tetrahydroisoquinoline moiety.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Tetrahydroisoquinolines
- Sub Class
- 4-phenyltetrahydroisoquinolines
- Direct Parent
- 4-phenyltetrahydroisoquinolines
- Alternative Parents
- Benzenesulfonamides / Benzenesulfonyl compounds / Aralkylamines / Organosulfonamides / Aryl chlorides / Aminosulfonyl compounds / Ureas / Trialkylamines / Dialkyl ethers / Azacyclic compounds show 4 more
- Substituents
- 4-phenyltetrahydroisoquinoline / Amine / Aminosulfonyl compound / Aralkylamine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenesulfonamide / Benzenesulfonyl group show 21 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- WYD79216A6
- CAS number
- 1234423-95-0
- InChI Key
- DNHPDWGIXIMXSA-CXNSMIOJSA-N
- InChI
- 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
- IUPAC Name
- 3-{2-[2-(2-{3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]benzenesulfonamido}ethoxy)ethoxy]ethyl}-1-{4-[({2-[2-(2-{3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]benzenesulfonamido}ethoxy)ethoxy]ethyl}carbamoyl)amino]butyl}urea
- SMILES
- CN1C[C@@H](C2=CC(=CC=C2)S(=O)(=O)NCCOCCOCCNC(=O)NCCCCNC(=O)NCCOCCOCCNS(=O)(=O)C2=CC(=CC=C2)[C@@H]2CN(C)CC3=C2C=C(Cl)C=C3Cl)C2=C(C1)C(Cl)=CC(Cl)=C2
References
- Synthesis Reference
Jindrich Richter, Ondrej Dammer, Lukas Krejcik, Ludmila Hejtmankova, Petr Lustig, Michal Dousa "Solid forms of tenapanor and method of preparation of tenapanor." WO Patent WO2019091503A1, issued May 2019.
- General References
- Johansson S, Rosenbaum DP, Ahlqvist M, Rollison H, Knutsson M, Stefansson B, Elebring M: Effects of Tenapanor on Cytochrome P450-Mediated Drug-Drug Interactions. Clin Pharmacol Drug Dev. 2017 Sep;6(5):466-475. doi: 10.1002/cpdd.346. Epub 2017 Mar 16. [Article]
- Zielinska M, Wasilewski A, Fichna J: Tenapanor hydrochloride for the treatment of constipation-predominant irritable bowel syndrome. Expert Opin Investig Drugs. 2015;24(8):1093-9. doi: 10.1517/13543784.2015.1054480. Epub 2015 Jun 12. [Article]
- Johansson SA, Knutsson M, Leonsson-Zachrisson M, Rosenbaum DP: Effect of Food Intake on the Pharmacodynamics of Tenapanor: A Phase 1 Study. Clin Pharmacol Drug Dev. 2017 Sep;6(5):457-465. doi: 10.1002/cpdd.341. Epub 2017 Mar 24. [Article]
- Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Bell N, Tabora J, Joly KM, Navre M, Jacobs JW, Charmot D: Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci Transl Med. 2014 Mar 12;6(227):227ra36. doi: 10.1126/scitranslmed.3007790. [Article]
- Labonte ED, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Dy E, Black D, Zhong Z, Langsetmo I, Spencer AG, Bell N, Deshpande D, Navre M, Lewis JG, Jacobs JW, Charmot D: Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD. J Am Soc Nephrol. 2015 May;26(5):1138-49. doi: 10.1681/ASN.2014030317. Epub 2014 Nov 17. [Article]
- FDA Approved Drug Products: Isbrela (tenapanor) tablets for oral use [Link]
- FDA Approved Drug Products: XPHOZAH (tenapanor) tablets, for oral use [Link]
- External Links
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Treatment Chronic Kidney Disease Requiring Chronic Dialysis / Hyperphosphataemia 1 4 Completed Treatment End Stage Renal Disease (ESRD) / Hyperphosphataemia 1 4 Recruiting Treatment Irritable Bowel Syndrome (IBS) 1 3 Completed Treatment Hyperphosphataemia 2 3 Completed Treatment Irritable Bowel Syndrome With Constipation (IBS-C) 3
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 50 mg Tablet Oral 53.2 mg/1 Tablet, film coated Oral 10.6 mg/1 Tablet, film coated Oral 21.3 mg/1 Tablet, film coated Oral 31.9 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9006281 No 2015-04-14 2030-05-02 US US9408840 No 2016-08-09 2029-12-30 US US8541448 No 2013-09-24 2029-12-30 US US8969377 No 2015-03-03 2029-12-30 US US10940146 No 2014-04-10 2034-04-10 US US10272079 No 2014-04-10 2034-04-10 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Practically insoluble FDA Label - Predicted Properties
Property Value Source Water Solubility 0.00292 mg/mL ALOGPS logP 4.55 ALOGPS logP 5.02 Chemaxon logS -5.6 ALOGPS pKa (Strongest Acidic) 9.86 Chemaxon pKa (Strongest Basic) 6.84 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 12 Chemaxon Hydrogen Donor Count 6 Chemaxon Polar Surface Area 218 Å2 Chemaxon Rotatable Bond Count 27 Chemaxon Refractivity 291.93 m3·mol-1 Chemaxon Polarizability 120.95 Å3 Chemaxon Number of Rings 6 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 317.89255 predictedDeepCCS 1.0 (2019) [M+H]+ 319.78796 predictedDeepCCS 1.0 (2019) [M+Na]+ 325.56592 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient (PubMed:26358773). Plays an important role in signal transduction.
- Specific Function
- Pdz domain binding
- Gene Name
- SLC9A3
- Uniprot ID
- P48764
- Uniprot Name
- Sodium/hydrogen exchanger 3
- Molecular Weight
- 92853.665 Da
References
- FDA Approved Drug Products: Isbrela (tenapanor) tablets for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: Isbrela (tenapanor) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Oxygen binding
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- FDA Approved Drug Products: Isbrela (tenapanor) tablets for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.
- Gene Name
- SLCO2B1
- Uniprot ID
- O94956
- Uniprot Name
- Solute carrier organic anion transporter family member 2B1
- Molecular Weight
- 76709.98 Da
References
- FDA Approved Drug Products: Isbrela (tenapanor) tablets for oral use [Link]
Drug created at October 20, 2016 20:45 / Updated at October 20, 2023 23:04