Ertugliflozin

Identification

Summary

Ertugliflozin is an SGLT2 inhibitor used to treat type 2 diabetes mellitus alone or in combination with other antidiabetic drugs.

Brand Names
Segluromet, Steglatro, Steglujan
Generic Name
Ertugliflozin
DrugBank Accession Number
DB11827
Background

Ertugliflozin is a sodium-dependent glucose cotransporter-2 (SGLT2) inhibitor used to treat type II diabetes mellitus. It works to block glucose reabsorption from the glomerulus.1

Ertugliflozin was first approved by the FDA in December 2017.5,6 It was also approved by the European Commission in March 2018.12

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 436.89
Monoisotopic: 436.1288808
Chemical Formula
C22H25ClO7
Synonyms
  • (1S,2S,3S,4R,5S)-5-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol
  • 1,6-Anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-5-C-(hydroxymethyl)-β-L-idopyranose
  • Ertugliflozin
  • β-L-Idopyranose, 1,6-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-5-C-(hydroxymethyl)-
External IDs
  • MK-8835
  • Pf 04971729
  • PF-04971729
  • PF-04971729-00
  • PF04971729

Pharmacology

Indication

Ertugliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus (T2DM).10 It is also available in combination with either metformin or sitagliptin.7,8

Ertugliflozin is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.10

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used as adjunct in combination to manageType 2 diabetes mellitusCombination Product in combination with: Metformin (DB00331)•••••••••••••••••••••••
Used as adjunct in combination to manageType 2 diabetes mellitusCombination Product in combination with: Sitagliptin (DB01261)•••••••••••••••••••••••
Adjunct therapy in management ofType ii diabetes mellitus•••••••••••••••••••••••••••••• ••••••••• •••••••••••••
Adjunct therapy in management ofType ii diabetes mellitus•••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Ertugliflozin causes a dose-dependent increase in urinary glucose excretion and an increase in urinary volume in patients with T2DM.3,10

Mechanism of action

Kidneys play an integral role in glucose homeostasis. After being filtered into urine within the nephron, most of the plasma glucose is reabsorbed through two types of sodium-dependent glucose cotransporters (SGLTs), SGLT1 and SGLT2, expressed in proximal renal tubules.4 More specifically, SGLT2 is responsible for 80–90% of renal glucose reabsorption while SGLT1 is responsible for the remaining 10-20%.4 Under physiological conditions, less than one percent of glucose is excreted in urine.1,4 In the case of hyperglycemia, SGLTs become saturated and the renal threshold for urinary glucose excretion is increased. Kidneys respond to an elevated threshold for glycosuria by elevating glucose reabsorption and increasing maximum glucose reabsorptive capacity.4

Ertugliflozin is an inhibitor of SGLT2 that reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion.10

TargetActionsOrganism
ASodium/glucose cotransporter 2
inhibitor
Humans
Absorption

After administering single doses of 5 mg and 15 mg ertugliflozin under fasted conditions, the median Tmax was one hour. Plasma Cmax and AUC of ertugliflozin increase dose-proportionally.10 Following administration of a 15 mg dose, the Cmax was 268 ng/mL and the AUC was 1193 ng h/mL.9 The absolute oral bioavailability of ertugliflozin following administration of a 15 mg dose was approximately 100%,10 though it is reported to range from 70% to 90%.2

Administration of ertugliflozin with a high-fat and high-calorie meal decreases ertugliflozin Cmax by 29%. It prolongs Tmax by one hour but does not alter AUC compared to the fasted state. The observed effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, and ertugliflozin may be administered with or without food.10

Volume of distribution

The volume of distribution following oral administration was 215.3 L.9 The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is 85.5 L.10

Protein binding

Ertugliflozin is 93.6% bound to plasma proteins. Plasma protein binding is independent of ertugliflozin plasma concentrations and is not meaningfully altered in patients with renal or hepatic impairment. The blood-to-plasma concentration ratio of ertugliflozin is 0.66.10

Metabolism

Ertugliflozin mainly undergoes O-glucuronidation mediated by UGT1A9 and UGT2B7 to form two pharmacologically inactive glucuronides. About 12% of the drug undergoes CYP-mediated oxidative metabolism.10 Several metabolites have been found in plasma, feces, and urine. In plasma, the unchanged form of ertugliflozin was found to be the major component of the administered dose.2

Hover over products below to view reaction partners

Route of elimination

Following administration of an oral [14C]-ertugliflozin solution to healthy subjects, approximately 40.9% and 50.2% of the drug-related radioactivity was eliminated in feces and urine, respectively. Only 1.5% of the administered dose was excreted as unchanged ertugliflozin in urine and 33.8% as unchanged ertugliflozin in feces, which is likely due to biliary excretion of glucuronide metabolites and subsequent hydrolysis to form the parent compound.10

Half-life

The terminal elimination half-life of ertugliflozin ranges from 11 to 17 hours.2 The mean elimination half-life in T2DM patients with normal renal function was estimated to be 16.6 hours based on the population pharmacokinetic analysis.10

Clearance

In one clinical involving healthy males, the apparent total plasma clearance rate after oral administration of ertugliflozin was 178.7 mL/min and the systemic total plasma clearance after intravenous administration was 187.2 ml/min.9 In another study, the mean systemic plasma clearance following an intravenous 100 µg dose was 11.2 L/hr.10

Adverse Effects
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Toxicity

The oral LD50 is 500 mg/kg in rats.11 There are limited clinical experiences of ertugliflozin overdose. It is recommended to initiate supportive measures in the event of drug overdosage. Removal of ertugliflozin by hemodialysis has not been studied.10

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
AcarboseErtugliflozin may increase the hypoglycemic activities of Acarbose.
AcebutololThe therapeutic efficacy of Ertugliflozin can be increased when used in combination with Acebutolol.
AcetazolamideThe therapeutic efficacy of Ertugliflozin can be increased when used in combination with Acetazolamide.
AcetohexamideErtugliflozin may increase the hypoglycemic activities of Acetohexamide.
Acetyl sulfisoxazoleThe therapeutic efficacy of Ertugliflozin can be increased when used in combination with Acetyl sulfisoxazole.
Food Interactions
  • Avoid excessive or chronic alcohol consumption. Alcohol abuse may increase the risk of ketoacidosis.
  • Take with or without food. Food does not significantly affect drug pharmacokinetics. Take the drug the morning.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Ertugliflozin pidolateMLU731K3211210344-83-4YHIUPZFKHZTLSH-LXYIGGQGSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SteglatroTablet, film coated15 mgOralMerck Sharp & Dohme B.V.2020-12-16Not applicableEU flag
SteglatroTablet, film coated5 mgOralMerck Sharp & Dohme B.V.2020-12-16Not applicableEU flag
SteglatroTablet, film coated15 mgOralMerck Sharp & Dohme B.V.2020-12-16Not applicableEU flag
SteglatroTablet, film coated5 mgOralMerck Sharp & Dohme B.V.2020-12-16Not applicableEU flag
SteglatroTablet, film coated15 mgOralMerck Sharp & Dohme B.V.2020-12-16Not applicableEU flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
SEGLUROMETErtugliflozin (2.5 MG) + Metformin hydrochloride (1000 MG)Tablet, film coatedOralMerck Sharp & Dohme B.V.2018-08-07Not applicableItaly flag
SeglurometErtugliflozin pidolate (2.5 mg) + Metformin hydrochloride (850 mg)Tablet, film coatedOralMerck Sharp & Dohme B.V.2020-12-16Not applicableEU flag
SEGLUROMETErtugliflozin (7.5 MG) + Metformin hydrochloride (1000 MG)Tablet, film coatedOralMerck Sharp & Dohme B.V.2018-08-07Not applicableItaly flag
SeglurometErtugliflozin pidolate (7.5 mg) + Metformin hydrochloride (850 mg)Tablet, film coatedOralMerck Sharp & Dohme B.V.2020-12-16Not applicableEU flag
SEGLUROMETErtugliflozin (2.5 MG) + Metformin hydrochloride (1000 MG)Tablet, film coatedOralMerck Sharp & Dohme B.V.2018-08-07Not applicableItaly flag

Categories

ATC Codes
A10BD23 — Metformin and ertugliflozinA10BK04 — ErtugliflozinA10BD24 — Sitagliptin and ertugliflozin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / Oxepanes / Chlorobenzenes / Ketals / Oxanes / Aryl chlorides / Monosaccharides / 1,3-dioxolanes
show 6 more
Substituents
Acetal / Alcohol / Alkyl aryl ether / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Chlorobenzene / Diphenylmethane / Ether / Halobenzene
show 17 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
6C282481IP
CAS number
1210344-57-2
InChI Key
MCIACXAZCBVDEE-CUUWFGFTSA-N
InChI
InChI=1S/C22H25ClO7/c1-2-28-16-6-3-13(4-7-16)9-14-10-15(5-8-17(14)23)22-20(27)18(25)19(26)21(11-24,30-22)12-29-22/h3-8,10,18-20,24-27H,2,9,11-12H2,1H3/t18-,19-,20+,21-,22-/m0/s1
IUPAC Name
(1S,2S,3S,4R,5S)-5-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol
SMILES
CCOC1=CC=C(CC2=CC(=CC=C2Cl)[C@]23OC[C@](CO)(O2)[C@@H](O)[C@H](O)[C@H]3O)C=C1

References

General References
  1. Miao Z, Nucci G, Amin N, Sharma R, Mascitti V, Tugnait M, Vaz AD, Callegari E, Kalgutkar AS: Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab Dispos. 2013 Feb;41(2):445-56. doi: 10.1124/dmd.112.049551. Epub 2012 Nov 20. [Article]
  2. Abdul-Ghani MA, DeFronzo RA: Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008 Sep;14(6):782-90. doi: 10.4158/EP.14.6.782. [Article]
  3. Kalgutkar AS, Tugnait M, Zhu T, Kimoto E, Miao Z, Mascitti V, Yang X, Tan B, Walsky RL, Chupka J, Feng B, Robinson RP: Preclinical species and human disposition of PF-04971729, a selective inhibitor of the sodium-dependent glucose cotransporter 2 and clinical candidate for the treatment of type 2 diabetes mellitus. Drug Metab Dispos. 2011 Sep;39(9):1609-19. doi: 10.1124/dmd.111.040675. Epub 2011 Jun 20. [Article]
  4. Cinti F, Moffa S, Impronta F, Cefalo CM, Sun VA, Sorice GP, Mezza T, Giaccari A: Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date. Drug Des Devel Ther. 2017 Oct 3;11:2905-2919. doi: 10.2147/DDDT.S114932. eCollection 2017. [Article]
  5. Markham A: Ertugliflozin: First Global Approval. Drugs. 2018 Mar;78(4):513-519. doi: 10.1007/s40265-018-0878-6. [Article]
  6. Pfizer: FDA Approves SGLT2 Inhibitor STEGLATRO™ (ertugliflozin) and Fixed-Dose Combination STEGLUJAN™ (ertugliflozin and sitagliptin) for Adults with Type 2 Diabetes [Link]
  7. FDA Approved Drug Products: Segluromet (ertugliflozin and metformin hydrochloride) tablets for oral use [Link]
  8. FDA Approved Drug Products: Steglujan (ertugliflozin and sitagliptin) tablets for oral use [Link]
  9. ClinicalTrials.gov: A Phase 1 Study of Ertugliflozin in Healthy Male Participants (MK-8835-020) [Link]
  10. FDA Approved Drug Products: STEGLATRO (ertugliflozin) tablets, for oral use (September 2023) [Link]
  11. MSD: Ertugliflozin MSDS [Link]
  12. EMA Approved Drug Products: STEGLATRO (ertugliflozin) Oral Tablets [Link]
PubChem Compound
44814423
PubChem Substance
347828173
ChemSpider
26340533
BindingDB
50342885
RxNav
1992672
ChEBI
188719
ChEMBL
CHEMBL1770248
ZINC
ZINC000068197809
PharmGKB
PA166269521
Wikipedia
Ertugliflozin

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
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableRecruitingNot AvailableMyocardial Infarction / Type 2 Diabetes Mellitus1somestatusstop reasonjust information to hide
Not AvailableUnknown StatusNot AvailableCardiovascular Events / Kidney Diseases / Type 2 Diabetes Mellitus1somestatusstop reasonjust information to hide
Not AvailableUnknown StatusNot AvailableType 2 Diabetes Mellitus1somestatusstop reasonjust information to hide
4Active Not RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19)1somestatusstop reasonjust information to hide
4CompletedPreventionDiabetic Kidney Disease (DKD) / Diabetic Nephropathy / Ertugliflozin / Kidney Hypoxia / Renoprotection / SGLT 2 Inhibitors / Type 2 Diabetes Mellitus1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
TabletOral15 mg
TabletOral5 mg
Tablet, film coatedOral15 mg/1
Tablet, film coatedOral5 mg/1
Tablet, film coatedOral
Tablet, film coatedOral15 mg
Tablet, film coatedOral5 mg
Tablet, coatedOral
Tablet, coatedOral15 mg
Tablet, coatedOral5 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7326708Yes2008-02-052027-05-24US flag
US6699871Yes2004-03-022023-01-26US flag
US6890898No2005-05-102019-02-02US flag
US7078381No2006-07-182019-02-02US flag
US7459428No2008-12-022019-02-02US flag
US8080580No2011-12-202030-07-13US flag
US9439902No2016-09-132030-10-21US flag
US9439901No2016-09-132030-10-21US flag
US9308204No2016-04-122030-10-21US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.119 mg/mLALOGPS
logP2.21ALOGPS
logP2.32Chemaxon
logS-3.6ALOGPS
pKa (Strongest Acidic)11.98Chemaxon
pKa (Strongest Basic)-3.1Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area108.61 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity109.07 m3·mol-1Chemaxon
Polarizability44.95 Å3Chemaxon
Number of Rings4Chemaxon
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/MSsplash10-000i-0001900000-ccc7b58f2866e09aa7ad
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-000i-0003900000-f23d448b27a3f152b544
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0104900000-a1d955d403bfa69c3a96
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0569-6009500000-dcf6ba56b71e5eac538d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00ks-1248900000-c65926e042a352ba73c1
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a5l-9037700000-09725bd7e490ac2a6061
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-195.2837
predicted
DeepCCS 1.0 (2019)
[M+H]+197.67929
predicted
DeepCCS 1.0 (2019)
[M+Na]+204.20786
predicted
DeepCCS 1.0 (2019)

Targets

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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
  1. Miao Z, Nucci G, Amin N, Sharma R, Mascitti V, Tugnait M, Vaz AD, Callegari E, Kalgutkar AS: Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab Dispos. 2013 Feb;41(2):445-56. doi: 10.1124/dmd.112.049551. Epub 2012 Nov 20. [Article]
  2. FDA Approved Drug Products: STEGLATRO (ertugliflozin) tablets, for oral use (September 2023) [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
  1. Sahasrabudhe V, Terra SG, Hickman A, Saur D, Shi H, O'Gorman M, Zhou Z, Cutler DL: The Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Ertugliflozin in Subjects With Type 2 Diabetes Mellitus. J Clin Pharmacol. 2017 Nov;57(11):1432-1443. doi: 10.1002/jcph.955. Epub 2017 Jul 13. [Article]
  2. FDA Approved Drug Products: STEGLATRO (ertugliflozin) tablets, for oral use (September 2023) [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
  1. Sahasrabudhe V, Terra SG, Hickman A, Saur D, Shi H, O'Gorman M, Zhou Z, Cutler DL: The Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Ertugliflozin in Subjects With Type 2 Diabetes Mellitus. J Clin Pharmacol. 2017 Nov;57(11):1432-1443. doi: 10.1002/jcph.955. Epub 2017 Jul 13. [Article]
  2. FDA Approved Drug Products: STEGLATRO (ertugliflozin) tablets, for oral use (September 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Ertugliflozin is a weak inhibitor of this enzyme in vitro, with an IC50 of >39 µM.
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
  1. FDA Approved Drug Products: STEGLATRO (ertugliflozin) tablets, for oral use (September 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Ertugliflozin is a weak inhibitor of this enzyme in vitro, with an IC50 of >39 µM.
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:18177842, PubMed:24641623). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:18177842). Involved in the glucuronidation of calcidiol, which is the major circulating form of vitamin D3 essential for the regulation of calcium and phosphate homeostasis (PubMed:24641623). Also glucuronidates the biologically active form of vitamin D3, calcitriol, probably leading to its biliary transport and intestinal reabsorption (PubMed:18177842)
Specific Function
enzyme binding
Gene Name
UGT1A4
Uniprot ID
P22310
Uniprot Name
UDP-glucuronosyltransferase 1A4
Molecular Weight
60024.535 Da
References
  1. FDA Approved Drug Products: STEGLATRO (ertugliflozin) tablets, for oral use (September 2023) [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
Specific Function
antioxidant activity
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Albumin
Molecular Weight
69365.94 Da
References
  1. Cinti F, Moffa S, Impronta F, Cefalo CM, Sun VA, Sorice GP, Mezza T, Giaccari A: Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date. Drug Des Devel Ther. 2017 Oct 3;11:2905-2919. doi: 10.2147/DDDT.S114932. eCollection 2017. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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
  1. FDA Approved Drug Products: STEGLATRO (ertugliflozin) tablets, for oral use (September 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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
  1. FDA Approved Drug Products: STEGLATRO (ertugliflozin) tablets, for oral use (September 2023) [Link]

Drug created at October 20, 2016 20:51 / Updated at November 03, 2024 19:35