Identification

Name
Ertugliflozin
Accession Number
DB11827
Type
Small Molecule
Groups
Approved, Investigational
Description

Ertugliflozin belongs to the class of potent and selective inhibitors of the sodium-dependent glucose cotransporters (SGLT), more specifically the type 2 which is responsible for about 90% of the glucose reabsorption from glomerulus.[1] This drug was developed under the collaboration of Merck and Pfizer. It was FDA approved as monotherapy and in combination with sitagliptin or metformin hydrochloride on December 22, 2017.[6]

Structure
Thumb
Synonyms
Not Available
External IDs
Pf 04971729 / PF-04971729-00
Product Ingredients
IngredientUNIICASInChI Key
Ertugliflozin pidolateMLU731K3211210344-83-4YHIUPZFKHZTLSH-LXYIGGQGSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SteglatroTablet, film coated5 mg/1OralMerck Sharp & Dohme Limited2017-12-19Not applicableUs
SteglatroTablet, film coated15 mg/1OralMerck Sharp & Dohme Limited2017-12-19Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
SeglurometErtugliflozin pidolate (7.5 mg/1) + Metformin Hydrochloride (1000 mg/1)Tablet, film coatedOralMerck Sharp & Dohme Limited2017-12-19Not applicableUs
SeglurometErtugliflozin pidolate (2.5 mg/1) + Metformin Hydrochloride (500 mg/1)Tablet, film coatedOralMerck Sharp & Dohme Limited2017-12-19Not applicableUs
SeglurometErtugliflozin pidolate (7.5 mg/1) + Metformin Hydrochloride (500 mg/1)Tablet, film coatedOralMerck Sharp & Dohme Limited2017-12-19Not applicableUs
SeglurometErtugliflozin pidolate (2.5 mg/1) + Metformin Hydrochloride (1000 mg/1)Tablet, film coatedOralMerck Sharp & Dohme Limited2017-12-19Not applicableUs
SteglujanErtugliflozin pidolate (15 mg/1) + Sitagliptin (100 mg/1)Tablet, film coatedOralMerck Sharp & Dohme Limited2017-12-19Not applicableUs
SteglujanErtugliflozin pidolate (5 mg/1) + Sitagliptin (100 mg/1)Tablet, film coatedOralMerck Sharp & Dohme Limited2017-12-19Not applicableUs
Categories
UNII
6C282481IP
CAS number
1210344-57-2
Weight
Average: 436.89
Monoisotopic: 436.1288808
Chemical Formula
C22H25ClO7
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

Pharmacology

Indication

Ertugliflozin as a monotherapy is indicated to improve the glycemic control in adult patients with type 2 diabetes.[Label] Ertugliflozin, in combination with metformin hydrochloride, is indicated to improve glycemic control in patients with diabetes type 2 who are not controlled on a regimen of ertugliflozin or metformin or in patients who are already treated with both ertugliflozin and metformin.[7] The administration of ertugliflozin in combination with sitagliptin is indicated to improve glycemic control in adult patients with type 2 diabetes when treatment with ertugliflozin and sitagliptin is appropriate.[8] It is pointed out that the use of ertugliflozin has to be an adjunct therapy to the use of diet and exercise. The type 2 diabetes mellitus is characterized by insulin resistance in muscle and liver, which results in the elevation of glucose levels in blood, or by presence of insulin deficiency. The insulin resistance is related to genetic factors, obesity, sedentary lifestyle or/and aging. This increase in the blood glucose can cause severe damage to kidney, eyes and vascular system.[2]

Associated Conditions
Pharmacodynamics

Administration of ertugliflozin increases urinary glucose excretion which leads to a negative balance and osmotic diuresis. Thus, this antidiabetic agent has been reported to significantly reduce the body weight and blood pressure of diabetic patients.[4]

Mechanism of action

As part of a normal process, the glucose from the blood is filtered for excretion and reabsorbed in the glomerulus so less than one percent of this glucose is excreted in the urine. The reabsorption is mediated by the sodium-dependent glucose cotransporter (SGLT), mainly the type 2 which is responsible for 90% of the reabsorbed glucose. Ertugliflozin is a small inhibitor of the SGLT2 and its activity increases glucose excretion, reducing hyperglycemia without the requirement of excessive insulin secretion.[1]

TargetActionsOrganism
ASodium/glucose cotransporter 2
antagonist
Human
Absorption

Preclinical studies showed that ertugliflozin is well absorbed and had an oral bioavailability of 70-90%. The reported Tmax occurred at 0.5-1.5 hours after dosage.[3] Following oral administration, the Cmax and AUC appeared to be dose proportional.Administration of 15 mg reported values of Cmax and AUC of 268 ng/ml and 1193 ng h/ml respectively.[9]

Volume of distribution

After oral administration of ertugliflozin, the apparent volume of distribution was reported to be 215.3 L. The steady-state volume of distribution after intravenous administration of etrugliflozin is 85.53 L.[9]

Protein binding

Ertugliflozin is highly bound to plasma proteins and it binds in a range of 94-96% independently of the administered concentration.[5]

Metabolism

In vitro studies showed that the metabolic profile of ertugliflozin in liver microsomes and hepatocytes is formed by reactions of monohydroxylation, O-demethylation and glucuronidation. The metabolism of ertugliflozin is proposed to be formed by 8 different metabolites found in plasma, feces and urine. In plasma, the unchanged form of ertugliflozin was found to be the major component of the administered dose. There were also other six minor metabolites identified in circulating plasma.[3]

Route of elimination

The total recovery of ertugliflozin was 91% and this elimination route is distributed in a ratio of 50% in the urine and 41% in feces. The recovery of the administered dose was achieved approximately 168 hours after initial administration. Urine elimination occurred very rapidly and 80% of the dosage recovered in urine was obtained after 24 hours. The eliminated dose in urine was composed of seven different major metabolites and the unchanged ertugliflozin as a minor metabolite. The elimination rate in feces was depending on the bowel movements of each patient but 98.5% of the eliminated dose in feces was obtained after 168 hours of initial dosage. This eliminated dose was formed mainly by unchanged ertugliflozin and three other minor metabolites.[2]

Half life

The terminal elimination half-life of ertugliflozin is 11-17 hours.[3]

Clearance

The apparent total plasma clearance rate after oral administration of ertugliflozin is 178.7 ml/min and the systemic total plasma clearance after intravenous administration is reported to be 187.2 ml/min.[9]

Toxicity

The reports from clinical trials have portrait ertugliflozin to be well tolerated and abscent of significant side effects.[5] Carcinogenic studies have been performed and it has been reported an increased incidence of adrenal medullary pheochromocytoma; possibly related to carbohydrate malabsorption leading to altered calcium homeostasis. There were no reported cases of mutagenesis or impairment in fertility.[Label]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenThe serum concentration of Ertugliflozin can be increased when it is combined with Acetaminophen.
AcetohexamideErtugliflozin may increase the hypoglycemic activities of Acetohexamide.
AmiodaroneThe serum concentration of Ertugliflozin can be increased when it is combined with Amiodarone.
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Ertugliflozin.
AmlodipineThe serum concentration of Ertugliflozin can be increased when it is combined with Amlodipine.
AmsacrineThe serum concentration of Ertugliflozin can be increased when it is combined with Amsacrine.
ApalutamideThe serum concentration of Ertugliflozin can be decreased when it is combined with Apalutamide.
AzithromycinThe serum concentration of Ertugliflozin can be increased when it is combined with Azithromycin.
Benzyl alcoholThe serum concentration of Ertugliflozin can be increased when it is combined with Benzyl alcohol.
BepridilThe serum concentration of Ertugliflozin can be increased when it is combined with Bepridil.
Food Interactions
Not Available

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. [PubMed:23169609]
  2. Dendup T, Feng X, Clingan S, Astell-Burt T: Environmental Risk Factors for Developing Type 2 Diabetes Mellitus: A Systematic Review. Int J Environ Res Public Health. 2018 Jan 5;15(1). pii: ijerph15010078. doi: 10.3390/ijerph15010078. [PubMed:29304014]
  3. 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. [PubMed:18996802]
  4. 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. [PubMed:21690265]
  5. 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. [PubMed:29042751]
  6. Pfizer News [Link]
  7. Segluromet [Link]
  8. Steglujan [Link]
  9. Clinical trials [Link]
External Links
PubChem Compound
44814423
PubChem Substance
347828173
ChemSpider
26340533
BindingDB
50342885
ChEMBL
CHEMBL1770248
Wikipedia
Ertugliflozin
FDA label
Download (779 KB)
MSDS
Download (23.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableAdults / Type 2 Diabetes Mellitus1
1CompletedNot AvailableHealthy Volunteers1
1CompletedNot AvailableType 2 Diabetes Mellitus1
1CompletedBasic ScienceType 2 Diabetes Mellitus1
1CompletedOtherHealthy Volunteers1
1CompletedTreatmentHepatic Impairment / Type 2 Diabetes Mellitus1
1CompletedTreatmentImpaired Renal Function / Type 2 Diabetes Mellitus1
1CompletedTreatmentType 2 Diabetes Mellitus1
2CompletedTreatmentHigh Blood Pressure (Hypertension) / Type 2 Diabetes Mellitus1
2CompletedTreatmentType 2 Diabetes Mellitus1
2Not Yet RecruitingTreatmentHeart Failure, Unspecified / Type 2 Diabetes Mellitus1
3Active Not RecruitingTreatmentType 2 Diabetes Mellitus1
3CompletedTreatmentType 2 Diabetes Mellitus8
4Not Yet RecruitingTreatmentHigh Blood Pressure (Hypertension) / Type 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral
Tablet, film coatedOral15 mg/1
Tablet, film coatedOral5 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7326708No2006-04-112026-04-11Us
US6699871No2002-07-262022-07-26Us
US6890898No1999-02-022019-02-02Us
US7078381No1999-02-022019-02-02Us
US7459428No1999-02-022019-02-02Us
US8080580No2010-07-132030-07-13Us
US9439902No2010-10-212030-10-21Us
US9439901No2010-10-212030-10-21Us
US9308204No2010-10-212030-10-21Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityVery slightly soluble'FDA label'
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/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

Taxonomy

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
Diphenylmethane / Phenoxy compound / Phenol ether / Halobenzene / Chlorobenzene / Oxepane / Ketal / Alkyl aryl ether / Monosaccharide / Oxane
show 17 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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. 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. [PubMed:23169609]

Enzymes

Kind
Protein
Organism
Human
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. 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. [PubMed:28703316]
Kind
Protein
Organism
Human
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. 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. [PubMed:28703316]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
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
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Protein homodimerization activity
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
UGT1A4
Uniprot ID
P22310
Uniprot Name
UDP-glucuronosyltransferase 1-4
Molecular Weight
60024.535 Da

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum 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. [PubMed:29042751]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
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

Drug created on October 20, 2016 14:51 / Updated on August 15, 2018 09:59