Sotagliflozin
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Identification
- Summary
Sotagliflozin is an orally administered dual SGLT1/2 inhibitor used alongside insulin to improve glycemic control in patients with type 1 diabetes mellitus.
- Brand Names
- Inpefa
- Generic Name
- Sotagliflozin
- DrugBank Accession Number
- DB12713
- Background
Sotagliflozin is a dual inhibitor of SGLT1 and SGLT2, the first of its kind,2 which is approved for use in the EU, in combination with insulin, to improve glycemic control in patients with type 1 diabetes mellitus (T1DM) and a BMI ≥27 kg/m2.3 Its potency in inhibiting SGLT2 is similar to that of other SGLT2 inhibitors, such as canagliflozin and dapagliflozin, but its potency in inhibiting SGLT1 is >10-fold higher than its predecessors.2 The added inhibition of intestinal SGLT1 delays glucose absorption in the distal small intestine and colon, thereby reducing post-prandial glucose levels.1,2
Sotagliflozin was approved by the EMA under the brand name "Zynquista" on April 26, 2019, for the treatment of type 1 diabetes.5 A similar approval has also been sought in the US, but the FDA has since published a proposal to refuse the approval because the data submitted did not show that it was safe under the proposed conditions of use.6 On March 22, 2022, the marketing authorization of sotagliflozin for the treatment of type 1 diabetes mellitus was withdrawn by the EMA due to commercial reasons.8
In May 2023, sotagliflozin was approved by the FDA to reduce the risk of cardiovascular death and heart failure in patients with high risk factors.[]
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 424.94
Monoisotopic: 424.1111228 - Chemical Formula
- C21H25ClO5S
- Synonyms
- Sotagliflozin
- External IDs
- LP-802034
- LX4211
Pharmacology
- Indication
In the US, sotagliflozin is indicated to reduce the risk of cardiovascular death and heart failure in adults with heart failure, type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors.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 Prevention of Cardiovascular mortality •••••••••••• ••••• •••••••••••••• •••• Prevention of Cardiovascular mortality •••••••••••• ••••• Prevention of Cardiovascular mortality •••••••••••• ••••• Prevention of Cardiovascular mortality •••••••••••• ••••• Prevention of Heart failure •••••••••••• ••••• ••••• ••••••• •• ••••• ••••••• - 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
Sotagliflozin exerts its pharmacologic effects by slowing glucose absorption in the gastrointestinal tract and increasing the excretion of glucose in the urine.3 It is administered by mouth once daily before the first meal of the day.
The use of SGLT2 inhibitors, including sotagliflozin, can cause diabetic ketoacidosis (DKA). Patients, especially those with a higher baseline risk of DKA, should be instructed on how and when to monitor for ketoacidosis and what actions to take when DKA is suspected.3
SGLT2 inhibitors, including sotagliflozin, also increase the risk of genital infections. This is due to the increase in urinary glucose excretion, which provides a relatively glucose-rich environment in which infectious agents may establish themselves.3
- Mechanism of action
Sodium-glucose co-transporter types 1 and 2 (SGLT1 and SGLT2) are integral in the transport of glucose in the body. SGLT1 is the major transporter for glucose absorption in the gastrointestinal tract,1 while SGLT2 is the predominant transporter responsible for reabsorption of glucose in the glomerulus.3
Sotagliflozin is a dual inhibitor of both SGLT1 and SGLT2.3 Inhibition of SGLT1 results in a delay in glucose absorption and a blunting of postprandial hyperglycemia, while inhibition of SGLT2 reduces renal reabsorption of filtered glucose, thereby increasing urinary glucose excretion.
Target Actions Organism ASodium/glucose cotransporter 2 inhibitorHumans ASodium/glucose cotransporter 1 inhibitorHumans - Absorption
Following a single dose, the Tmax of sotagliflozin ranged from 1.25 to 3 hours.3 Following multiple doses, the Tmax ranged from 2.5 to 4 hours.3 The estimated oral bioavailability of sotagliflozin is 71%.3
- Volume of distribution
Sotagliflozin has a mean apparent volume of distribution of 9392 L.3
- Protein binding
Both sotagliflozin and its major metabolite, M19, are extensively (~98%) protein-bound in plasma, although the specific protein(s) to which they bind have not been elucidated.3
- Metabolism
The major metabolite of sotagliflozin is a 3-O-glucuronide (M19), which comprised ~94% of of the radioactivity in plasma following the oral administration of a radiolabeled dose of sotagliflozin.3 The M19 metabolite is effectively inactive, with >275-fold less activity at SGLT1 and SGLT2 compared to the parent drug.4
The primary route of metabolism is via glucuronidation by UGT1A9 (and both UGT1A1 and UGT2B7, to a lesser extent) as well as oxidation via CYP3A4.3
Hover over products below to view reaction partners
- Route of elimination
Sotagliflozin is primarily eliminated via the renal route, with 57% of administered drug material appearing in the urine and 37% appearing in the feces.3
- Half-life
The mean terminal half-life of sotagliflozin ranged from 21 to 35 hours and from 19 to 26 hours for its M19 metabolite.3
- Clearance
In healthy volunteers, the mean apparent clearance of sotagliflozin ranged from 261 to 374 L/h.3 The mean apparent clearance estimated in a population of mostly type 1 diabetic patients was 239 L/h.3
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Multiple doses of 800mg once daily (double the maximum recommended dose) have been administered to healthy volunteers without evidence of overdose symptoms.3 In the event of a suspected overdose, administer supportive treatment as clinically indicated.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- 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 softwareAbemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Sotagliflozin. Acarbose The risk or severity of hypoglycemia can be increased when Acarbose is combined with Sotagliflozin. Acebutolol The therapeutic efficacy of Sotagliflozin can be increased when used in combination with Acebutolol. Acetazolamide The therapeutic efficacy of Sotagliflozin can be increased when used in combination with Acetazolamide. Acetohexamide The risk or severity of hypoglycemia can be increased when Acetohexamide is combined with Sotagliflozin. - Food Interactions
- Take before a meal. Sotagliflozin should be taken once daily before the first meal of the day.
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.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Inpefa Tablet 200 mg/1 Oral Lexicon Pharmaceuticals, Inc. 2023-05-26 Not applicable US Inpefa Tablet 200 mg/1 Oral Lexicon Pharmaceuticals, Inc. 2023-05-26 Not applicable US Inpefa Tablet 400 mg/1 Oral Lexicon Pharmaceuticals, Inc. 2023-05-26 Not applicable US Inpefa Tablet 400 mg/1 Oral Lexicon Pharmaceuticals, Inc. 2023-05-26 2023-05-26 US Zynquista Tablet, film coated 200 mg Oral Guidehouse Germany Gmb H 2020-12-16 2019-02-27 EU
Categories
- ATC Codes
- A10BK06 — Sotagliflozin
- Drug Categories
- Alimentary Tract and Metabolism
- BCRP/ABCG2 Inhibitors
- Blood Glucose Lowering Agents
- Cytochrome P-450 CYP2D6 Inhibitors
- Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strength unknown)
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Diuretics
- Drugs Used in Diabetes
- OATP1B1/SLCO1B1 Inhibitors
- OATP1B3 inhibitors
- P-glycoprotein inhibitors
- Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors
- Sodium-Glucose Transporter 1, antagonists & inhibitors
- Sodium-Glucose Transporter 2 Inhibitors
- UGT1A1 Substrates
- UGT1A9 Substrates
- UGT2B7 substrates
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenolic glycosides. These are organic compounds containing a phenolic structure attached to a glycosyl moiety. Some examples of phenolic structures include lignans, and flavonoids. Among the sugar units found in natural glycosides are D-glucose, L-Fructose, and L rhamnose.
- Kingdom
- Organic compounds
- Super Class
- Organic oxygen compounds
- Class
- Organooxygen compounds
- Sub Class
- Carbohydrates and carbohydrate conjugates
- Direct Parent
- Phenolic glycosides
- Alternative Parents
- Diphenylmethanes / Thioglycosides / Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / Chlorobenzenes / Aryl chlorides / Oxanes / Monosaccharides / Monothioacetals show 6 more
- Substituents
- Alcohol / Alkyl aryl ether / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Benzenoid / Chlorobenzene / Diphenylmethane / Ether / Halobenzene show 17 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 6B4ZBS263Y
- CAS number
- 1018899-04-1
- InChI Key
- QKDRXGFQVGOQKS-CRSSMBPESA-N
- InChI
- InChI=1S/C21H25ClO5S/c1-3-26-15-7-4-12(5-8-15)10-14-11-13(6-9-16(14)22)20-18(24)17(23)19(25)21(27-20)28-2/h4-9,11,17-21,23-25H,3,10H2,1-2H3/t17-,18-,19+,20+,21-/m1/s1
- IUPAC Name
- (2S,3R,4R,5S,6R)-2-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-6-(methylsulfanyl)oxane-3,4,5-triol
- SMILES
- CCOC1=CC=C(CC2=CC(=CC=C2Cl)[C@@H]2O[C@H](SC)[C@@H](O)[C@H](O)[C@H]2O)C=C1
References
- Synthesis Reference
Zhao MM, Zhang H, Iimura S, Bednarz MS, Song Q, Lim N, Yan J, Wu W, Dai K, Gu X, Wang Y: Process Development of Sotagliflozin, a Dual Inhibitor of Sodium–Glucose Cotransporter-1/2 for the Treatment of Diabetes Org Process Res Dev. 2020 Oct 7;24(11):2689-2701.
- General References
- Lapuerta P, Zambrowicz B, Strumph P, Sands A: Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. Diab Vasc Dis Res. 2015 Mar;12(2):101-10. doi: 10.1177/1479164114563304. [Article]
- Cefalo CMA, Cinti F, Moffa S, Impronta F, Sorice GP, Mezza T, Pontecorvi A, Giaccari A: Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovasc Diabetol. 2019 Feb 28;18(1):20. doi: 10.1186/s12933-019-0828-y. [Article]
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
- FDA Endocrinologic And Metabolic Drugs Advisory Committee: Sotagliflozin for the Treatment of Type 1 Diabetes [Link]
- EMA European Public Assessment Report: Zynquista (sotagliflozin) [Link]
- US Federal Register: Proposal To Refuse To Approve a New Drug Application for Sotagliflozin Oral Tablets, 200 Milligrams and 400 Milligrams; Opportunity for a Hearing [Link]
- FDA Approved Drug Products: INPEFA (sotagliflozin) tablets, for oral use (May 2023) [Link]
- EMA Public Statement: Zynquista Withdrawal of the marketing authorisation in the European Union [Link]
- External Links
- PubChem Compound
- 24831714
- PubChem Substance
- 347828911
- ChemSpider
- 27289071
- BindingDB
- 50235017
- 2638675
- ChEMBL
- CHEMBL3039507
- ZINC
- ZINC000095641922
- PDBe Ligand
- LFL
- Wikipedia
- Sotagliflozin
- PDB Entries
- 8hg7
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Not Yet Recruiting Not Available Sarcoidosis, Cardiac 1 somestatus stop reason just information to hide Not Available Not Yet Recruiting Treatment Cardiovascular Disease (CVD) / Heart Failure / Kidney Failure / Type 1 Diabetes Mellitus 1 somestatus stop reason just information to hide 4 Not Yet Recruiting Treatment Albuminuria / Diabetic complications cardiovascular / Diabetic complications renal / Diabetic Nephropathy / Glomerulonephritis / Hypoxia / Type 1 Diabetes Mellitus 1 somestatus stop reason just information to hide 4 Not Yet Recruiting Treatment Thrombosis 1 somestatus stop reason just information to hide 4 Recruiting Treatment Heart Failure With Preserved Ejection Fraction (HFpEF) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 200 mg/1 Tablet Oral 400 mg/1 Tablet, film coated Oral 200 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8217156 No 2012-07-10 2030-10-07 US US7781577 No 2010-08-24 2028-05-04 US US8476413 No 2013-07-02 2028-05-29 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.042 mg/mL ALOGPS logP 3.19 ALOGPS logP 3.73 Chemaxon logS -4 ALOGPS pKa (Strongest Acidic) 12.47 Chemaxon pKa (Strongest Basic) -3.7 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 79.15 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 110.87 m3·mol-1 Chemaxon Polarizability 44.93 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-0002900000-478a8abbe85c7e279adc Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-00di-2009800000-fa3d65869c3912c814a4 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0550-0494300000-d2ae6ac8e3f4af89d4a1 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9106100000-ebcf0315522502b4d98a Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-003r-6359100000-b580a97549b7e6684215 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0bvl-9178200000-e6ba460ca55ce0a500cc Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 188.4029 predictedDeepCCS 1.0 (2019) [M+H]+ 190.79846 predictedDeepCCS 1.0 (2019) [M+Na]+ 197.3679 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Electrogenic Na(+)-coupled sugar symporter that actively transports D-glucose at the plasma membrane, with a Na(+) to sugar coupling ratio of 1:1. Transporter activity is driven by a transmembrane Na(+) electrochemical gradient set by the Na(+)/K(+) pump (PubMed:20980548, PubMed:28592437, PubMed:34880493). Has a primary role in D-glucose reabsorption from glomerular filtrate across the brush border of the early proximal tubules of the kidney (By similarity)
- Specific Function
- alpha-glucoside transmembrane transporter activity
- Gene Name
- SLC5A2
- Uniprot ID
- P31639
- Uniprot Name
- Sodium/glucose cotransporter 2
- Molecular Weight
- 72895.995 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Electrogenic Na(+)-coupled sugar symporter that actively transports D-glucose or D-galactose at the plasma membrane, with a Na(+) to sugar coupling ratio of 2:1. Transporter activity is driven by a transmembrane Na(+) electrochemical gradient set by the Na(+)/K(+) pump (PubMed:20980548, PubMed:34880492, PubMed:35077764, PubMed:8563765). Has a primary role in the transport of dietary monosaccharides from enterocytes to blood. Responsible for the absorption of D-glucose or D-galactose across the apical brush-border membrane of enterocytes, whereas basolateral exit is provided by GLUT2. Additionally, functions as a D-glucose sensor in enteroendocrine cells, triggering the secretion of the incretins GCG and GIP that control food intake and energy homeostasis (By similarity) (PubMed:8563765). Together with SGLT2, functions in reabsorption of D-glucose from glomerular filtrate, playing a nonredundant role in the S3 segment of the proximal tubules (By similarity). Transports D-glucose into endometrial epithelial cells, controlling glycogen synthesis and nutritional support for the embryo as well as the decidual transformation of endometrium prior to conception (PubMed:28974690). Acts as a water channel enabling passive water transport across the plasma membrane in response to the osmotic gradient created upon sugar and Na(+) uptake. Has high water conductivity, comparable to aquaporins, and therefore is expected to play an important role in transepithelial water permeability, especially in the small intestine
- Specific Function
- alpha-glucoside transmembrane transporter activity
- Gene Name
- SLC5A1
- Uniprot ID
- P13866
- Uniprot Name
- Sodium/glucose cotransporter 1
- Molecular Weight
- 73497.275 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15470161, PubMed:15472229, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:19545173). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:20610558). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A9
- Uniprot ID
- O60656
- Uniprot Name
- UDP-glucuronosyltransferase 1A9
- Molecular Weight
- 59940.495 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808, PubMed:24525562). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1A1
- Molecular Weight
- 59590.91 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:10702251, PubMed:15470161, PubMed:15472229, PubMed:17442341, PubMed:18674515, PubMed:18719240, PubMed:19022937, PubMed:23288867, PubMed:23756265, PubMed:26220143). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:15470161, PubMed:18674515, PubMed:23756265). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (epitestosterone, androsterone) and estrogens (estradiol, epiestradiol, estriol, catechol estrogens) (PubMed:15472229, PubMed:17442341, PubMed:18719240, PubMed:19022937, PubMed:2159463, PubMed:23288867, PubMed:26220143). Also regulates the levels of retinoic acid, a major metabolite of vitamin A involved in apoptosis, cellular growth and differentiation, and embryonic development (PubMed:10702251). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, caderastan and zolarsatan, drugs which can inhibit the effect of angiotensin II (PubMed:18674515). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161)
- Specific Function
- glucuronosyltransferase activity
- Gene Name
- UGT2B7
- Uniprot ID
- P16662
- Uniprot Name
- UDP-glucuronosyltransferase 2B7
- Molecular Weight
- 60720.15 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitorInducer
- Curator comments
- M19 (the main metabolite of sotagliflozin) is both an inducer and inhibitor of CYP3A4.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- M19 (the main metabolite of sotagliflozin) is an inhibitor of CYP2D6.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
- Specific Function
- anandamide 11,12 epoxidase activity
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- Demonstrated in vitro.
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- Demonstrated in vitro.
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- M19 (the main metabolite of sotagliflozin) has demonstrated inhibitory effects against OATP1B1 in vitro.
- General Function
- Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1B1
- Uniprot ID
- Q9Y6L6
- Uniprot Name
- Solute carrier organic anion transporter family member 1B1
- Molecular Weight
- 76447.99 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- M19 (the main metabolite of sotagliflozin) has demonstrated inhibitory effects against OATP1B3 in vitro.
- General Function
- Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1B3
- Uniprot ID
- Q9NPD5
- Uniprot Name
- Solute carrier organic anion transporter family member 1B3
- Molecular Weight
- 77402.175 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- M19 (the main metabolite of sotagliflozin) has demonstrated inhibitory effects against MRP2 in vitro.
- General Function
- ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:10220572, PubMed:10421658, PubMed:11500505, PubMed:16332456). Mediates hepatobiliary excretion of mono- and bis-glucuronidated bilirubin molecules and therefore play an important role in bilirubin detoxification (PubMed:10421658). Mediates also hepatobiliary excretion of others glucuronide conjugates such as 17beta-estradiol 17-glucosiduronic acid and leukotriene C4 (PubMed:11500505). Transports sulfated bile salt such as taurolithocholate sulfate (PubMed:16332456). Transports various anticancer drugs, such as anthracycline, vinca alkaloid and methotrexate and HIV-drugs such as protease inhibitors (PubMed:10220572, PubMed:11500505, PubMed:12441801). Confers resistance to several anti-cancer drugs including cisplatin, doxorubicin, epirubicin, methotrexate, etoposide and vincristine (PubMed:10220572, PubMed:11500505)
- Specific Function
- ABC-type glutathione S-conjugate transporter activity
- Gene Name
- ABCC2
- Uniprot ID
- Q92887
- Uniprot Name
- ATP-binding cassette sub-family C member 2
- Molecular Weight
- 174205.64 Da
References
- EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
Drug created at October 20, 2016 23:45 / Updated at May 31, 2023 07:30