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.

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 in the EU under the brand name "Zynquista" on April 26, 2019.5 A similar approval has also been sought in the US, but the FDA has since published a proposal to refuse the approval on the grounds that the data submitted did not show that it was safe under the proposed conditions of use.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 424.94
Monoisotopic: 424.1111228
Chemical Formula
C21H25ClO5S
Synonyms
  • Sotagliflozin
External IDs
  • LP-802034
  • LX4211

Pharmacology

Indication

Sotagliflozin is indicated in the EU as an adjunct to insulin therapy to improve glycemic control in adults with type 1 diabetes and a BMI ≥27 kg/m2 who have been unable to achieve adequate glycemic control despite optimal insulin therapy.3

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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.

TargetActionsOrganism
ASodium/glucose cotransporter 2
inhibitor
Humans
ASodium/glucose cotransporter 1
inhibitor
Humans
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
Adverseeffects
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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.
DrugInteraction
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Sotagliflozin.
AcarboseThe risk or severity of hypoglycemia can be increased when Acarbose is combined with Sotagliflozin.
AcebutololThe therapeutic efficacy of Sotagliflozin can be increased when used in combination with Acebutolol.
AcetazolamideThe therapeutic efficacy of Sotagliflozin can be increased when used in combination with Acetazolamide.
AcetohexamideThe risk or severity of hypoglycemia can be increased when Acetohexamide is combined with Sotagliflozin.
Acetyl sulfisoxazoleThe therapeutic efficacy of Sotagliflozin can be increased when used in combination with Acetyl sulfisoxazole.
Acetylsalicylic acidThe risk or severity of hypoglycemia can be increased when Acetylsalicylic acid is combined with Sotagliflozin.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Sotagliflozin.
AlbiglutideThe risk or severity of hypoglycemia can be increased when Albiglutide is combined with Sotagliflozin.
AlclometasoneThe risk or severity of hyperglycemia can be increased when Alclometasone is combined with Sotagliflozin.
Interactions
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Food Interactions
  • Take before a meal. Sotagliflozin should be taken once daily before the first meal of the day.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZynquistaTablet, film coated200 mgOralGuidehouse Germany Gmb H2020-12-16Not applicableEU flag
ZynquistaTablet, film coated200 mgOralGuidehouse Germany Gmb H2020-12-16Not applicableEU flag
ZynquistaTablet, film coated200 mgOralGuidehouse Germany Gmb H2020-12-16Not applicableEU flag
ZynquistaTablet, film coated200 mgOralGuidehouse Germany Gmb H2020-12-16Not applicableEU flag
ZynquistaTablet, film coated200 mgOralGuidehouse Germany Gmb H2020-12-16Not applicableEU flag
ZynquistaTablet, film coated200 mgOralGuidehouse Germany Gmb H2020-12-16Not applicableEU flag
ZynquistaTablet, film coated200 mgOralGuidehouse Germany Gmb H2020-12-16Not applicableEU flag
ZynquistaTablet, film coated200 mgOralGuidehouse Germany Gmb H2020-12-16Not applicableEU flag

Categories

ATC Codes
A10BK06 — Sotagliflozin
Drug Categories
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
  1. 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]
  2. 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]
  3. EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
  4. FDA Endocrinologic And Metabolic Drugs Advisory Committee: Sotagliflozin for the Treatment of Type 1 Diabetes [Link]
  5. EMA European Public Assessment Report: Zynquista (sotagliflozin) [Link]
  6. 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]
PubChem Compound
24831714
PubChem Substance
347828911
ChemSpider
27289071
BindingDB
50235017
ChEMBL
CHEMBL3039507
ZINC
ZINC000095641922
Wikipedia
Sotagliflozin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentChronic Kidney Disease, Stage 3 (Moderate) / Type 2 Diabetes Mellitus1
3CompletedTreatmentHyperglycemia / Type 1 Diabetes Mellitus1
3CompletedTreatmentStage 4 Chronic Kidney Disease / Type 2 Diabetes Mellitus1
3CompletedTreatmentType 1 Diabetes Mellitus2
3CompletedTreatmentType 2 Diabetes Mellitus6
3TerminatedPreventionChronic Kidney Disease (CKD) / Type 2 Diabetes Mellitus1
3TerminatedTreatmentHeart Failure / Type 2 Diabetes Mellitus1
3TerminatedTreatmentType 2 Diabetes Mellitus3
2CompletedTreatmentDiabetes Mellitus1
2CompletedTreatmentType 1 Diabetes Mellitus3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral200 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.042 mg/mLALOGPS
logP3.19ALOGPS
logP3.73ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)12.47ChemAxon
pKa (Strongest Basic)-3.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area79.15 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity110.87 m3·mol-1ChemAxon
Polarizability44.93 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Low-affinity glucose:sodium symporter activity
Specific Function
Sodium-dependent glucose transporter. Has a Na(+) to glucose coupling ratio of 1:1.Efficient substrate transport in mammalian kidney is provided by the concerted action of a low affinity high capac...
Gene Name
SLC5A2
Uniprot ID
P31639
Uniprot Name
Sodium/glucose cotransporter 2
Molecular Weight
72895.995 Da
References
  1. 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
Glucose:sodium symporter activity
Specific Function
Actively transports glucose into cells by Na(+) cotransport with a Na(+) to glucose coupling ratio of 2:1. Efficient substrate transport in mammalian kidney is provided by the concerted action of a...
Gene Name
SLC5A1
Uniprot ID
P13866
Uniprot Name
Sodium/glucose cotransporter 1
Molecular Weight
73497.275 Da
References
  1. 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
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. 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
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. 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
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
References
  1. EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Inducer
Curator comments
M19 (the main metabolite of sotagliflozin) is both an inducer and inhibitor of CYP3A4.
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
  1. 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
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. 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
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. 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
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. 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
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. 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
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. 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
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
References
  1. EMA Summary of Product Characteristics: Zynquista (sotagliflozin) film-coated tablets for oral use [Link]

Drug created at October 20, 2016 23:45 / Updated at January 15, 2022 11:30