Identification

Name
Canagliflozin
Accession Number
DB08907
Type
Small Molecule
Groups
Approved
Description

Canagliflozin belongs to a new class of anti-diabetic drugs that works by inhibiting the sodium-glucose transport protein (SGLT2). This transport protein is found in the kidney and is responsible for reabsorbing glucose that has been filtered. FDA approved on March 29, 2013.

Structure
Thumb
Synonyms
  • Canagliflozin anhydrous
Product Ingredients
IngredientUNIICASInChI Key
Canagliflozin hydrate0SAC974Z85928672-86-0VHOFTEAWFCUTOS-TUGBYPPCSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
InvokanaTablet, film coated300 mg/1OralJanssen Pharmaceuticals, Inc.2013-03-29Not applicableUs50458 0141 30 nlmimage10 a344d186
InvokanaTablet100 mgOralJanssen Pharmaceuticals2014-06-03Not applicableCanada
InvokanaTablet, film coated100 mg/1OralJanssen Pharmaceuticals, Inc.2013-03-29Not applicableUs50458 0140 90 nlmimage10 4744a395
InvokanaTablet300 mgOralJanssen Pharmaceuticals2014-05-28Not applicableCanada
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
InvokametCanagliflozin (150 mg) + Metformin Hydrochloride (1000 mg)TabletOralJanssen Pharmaceuticals2016-06-28Not applicableCanada
InvokametCanagliflozin (50 mg) + Metformin Hydrochloride (500 mg)TabletOralJanssen Pharmaceuticals2016-06-28Not applicableCanada
InvokametCanagliflozin hydrate (150 mg/1) + Metformin Hydrochloride (500 mg/1)Tablet, film coatedOralJanssen Pharmaceuticals2014-08-08Not applicableUs
InvokametCanagliflozin (150 mg) + Metformin Hydrochloride (850 mg)TabletOralJanssen Pharmaceuticals2016-06-28Not applicableCanada
InvokametCanagliflozin (150 mg) + Metformin Hydrochloride (500 mg)TabletOralJanssen Pharmaceuticals2016-06-28Not applicableCanada
InvokametCanagliflozin hydrate (50 mg/1) + Metformin Hydrochloride (1000 mg/1)Tablet, film coatedOralJanssen Pharmaceuticals2014-08-08Not applicableUs
InvokametCanagliflozin (50 mg) + Metformin Hydrochloride (850 mg)TabletOralJanssen Pharmaceuticals2016-06-28Not applicableCanada
InvokametCanagliflozin (50 mg) + Metformin Hydrochloride (1000 mg)TabletOralJanssen Pharmaceuticals2016-06-28Not applicableCanada
InvokametCanagliflozin hydrate (150 mg/1) + Metformin Hydrochloride (1000 mg/1)Tablet, film coatedOralJanssen Pharmaceuticals2014-08-08Not applicableUs
InvokametCanagliflozin hydrate (50 mg/1) + Metformin Hydrochloride (500 mg/1)Tablet, film coatedOralJanssen Pharmaceuticals2014-08-08Not applicableUs
Categories
UNII
6S49DGR869
CAS number
842133-18-0
Weight
Average: 444.516
Monoisotopic: 444.140672805
Chemical Formula
C24H25FO5S
InChI Key
XTNGUQKDFGDXSJ-ZXGKGEBGSA-N
InChI
InChI=1S/C24H25FO5S/c1-13-2-3-15(24-23(29)22(28)21(27)19(12-26)30-24)10-16(13)11-18-8-9-20(31-18)14-4-6-17(25)7-5-14/h2-10,19,21-24,26-29H,11-12H2,1H3/t19-,21-,22+,23-,24+/m1/s1
IUPAC Name
(2S,3R,4R,5S,6R)-2-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-6-(hydroxymethyl)oxane-3,4,5-triol
SMILES
[H][C@]1(O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)C1=CC=C(C)C(CC2=CC=C(S2)C2=CC=C(F)C=C2)=C1

Pharmacology

Indication

Canagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Use in type 1 diabetes mellitus patients or in treatment of diabetic ketoacidosis is not recommended.

Associated Conditions
Pharmacodynamics

Canagliflozin binds to SGLT2 more potently (250-times) than SGLT1 in vitro. The 50% inhibitory concentrations (IC50) are 2.2-4.4 nmol/L and 684 - 910 nmol/L for SGLT2 and SGLT1 respectively. Dose dependent decreases in renal threshold for glucose and increases in urinary glucose excretion were observed when single and multiple oral doses were administered to type 2 diabetes patients. Decreases in plasma glucose in a dose-dependent fashion were also noted as early as the first day of administration. When given to healthy and type 2 diabetic patients before a meal, a delay in intestinal glucose absorption and a reduction in postprandial glucose was observed. Canagliflozin does not prolong the QTc interval.

Mechanism of action

Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion.

TargetActionsOrganism
ASodium/glucose cotransporter 2
inhibitor
Human
USodium/glucose cotransporter 1
inhibitor
Human
Absorption

The pharmacokinetics of canagliflozin is similar in healthy subjects and patients with type 2 diabetes. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. Accumulation in plasma has been observed following multiple doses of 100 - 300 mg. Food does not affect the absorption of canagliflozin. Tmax = 1- 2 hours; Cmax = 1059 - 3148 ng/mL; Time to steady state, once daily dose, 100 - 300 mg = 4-5 days; Absolute oral bioavailability = 65%.

Volume of distribution

Steady state, single IV infusion, healthy subject = 119 L. This high value suggests that cangliflozin is extensively distributed to tissue.

Protein binding

>99% protein bound, mainly to albumin. It also binds to alpha-acid glycoprotein. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.

Metabolism

Canagliflozin is hepatically metabolized via O-glucuronidation into two inactive O-glucuronide metabolites. The enzymes that facilitate this process are UGT1A9 and UGT2B4. To a lesser extent (7%), canagliflozin also undergoes oxidative metabolism via CYP3A4. Canagliflozin weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes.

Route of elimination

Enterohepatic circulation of canagliflozin was negligible. When a single oral dose is administered to a healthy subject, canagliflozin is eliminated via the following: Feces (41.5%, 7.0%, 3.2% as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively). Urine (33%; 30.5% as O-glucuronide metabolite, <1% as unchanged drug).

Half life

The apparent terminal half-life (t1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively.

Clearance

Mean systemic clearance, healthy subjects, IV administration = 192 mL/min. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min.

Toxicity

Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination.

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

Interactions

Drug Interactions
DrugInteraction
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypoglycemic activities of Canagliflozin.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Canagliflozin.
AcetaminophenThe serum concentration of Canagliflozin can be increased when it is combined with Acetaminophen.
AcetazolamideThe therapeutic efficacy of Canagliflozin can be increased when used in combination with Acetazolamide.
AcetohexamideCanagliflozin may increase the hypoglycemic activities of Acetohexamide.
Acetyl sulfisoxazoleThe metabolism of Canagliflozin can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidAcetylsalicylic acid may increase the hypoglycemic activities of Canagliflozin.
AcyclovirAcyclovir may decrease the excretion rate of Canagliflozin which could result in a higher serum level.
Adefovir DipivoxilAdefovir Dipivoxil may decrease the excretion rate of Canagliflozin which could result in a higher serum level.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Canagliflozin.
Food Interactions
Not Available

References

General References
  1. Lamos EM, Younk LM, Davis SN: Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin Drug Metab Toxicol. 2013 Jun;9(6):763-75. doi: 10.1517/17425255.2013.791282. Epub 2013 Apr 17. [PubMed:23590413]
External Links
KEGG Drug
D09592
PubChem Compound
24812758
PubChem Substance
175427146
ChemSpider
26333259
BindingDB
50386885
ChEBI
73274
ChEMBL
CHEMBL2048484
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Canagliflozin
ATC Codes
A10BX11 — CanagliflozinA10BD16 — Metformin and canagliflozin
AHFS Codes
  • 68:20.18 — Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors
FDA label
Download (683 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers7
1CompletedNot AvailableHealthy Volunteers / Hepatic Insufficiency1
1CompletedOtherHealthy Volunteers2
1CompletedTreatmentBioequivalence1
1CompletedTreatmentHealthy Volunteers24
1CompletedTreatmentHealthy Volunteers / Impaired Renal Function1
1CompletedTreatmentPlasma Volume / Type 2 Diabetes Mellitus1
1CompletedTreatmentType 2 Diabetes Mellitus7
1Enrolling by InvitationBasic ScienceType 2 Diabetes Mellitus1
1RecruitingOtherDiabetes Mellitus (DM) / Fibroblast Growth Factor (FGF23) / Phosphate / PTH / Vitamin D1
1, 2CompletedTreatmentType 2 Diabetes Mellitus1
2CompletedTreatmentBMI >30 kg/m22
2CompletedTreatmentDiabetes Mellitus, Non Insulin Dependent / Type 2 Diabetes Mellitus1
2CompletedTreatmentDiabetes, Diabetes Mellitus Type 11
2CompletedTreatmentType 2 Diabetes Mellitus1
3Active Not RecruitingTreatmentDiabetes Mellitus (DM) / Type 2 Diabetes Mellitus1
3Active Not RecruitingTreatmentDiabetic Nephropathies / Type 2 Diabetes Mellitus1
3CompletedTreatmentCardiovascular Disease (CVD) / Risk Factors / Type 2 Diabetes Mellitus1
3CompletedTreatmentImpaired Renal Function / Type 2 Diabetes Mellitus1
3CompletedTreatmentType 2 Diabetes Mellitus14
3RecruitingTreatmentDiabetic Nephropathies1
3RecruitingTreatmentType 2 Diabetes Mellitus1
4CompletedTreatmentAlbuminuria / Type 2 Diabetes Mellitus1
4CompletedTreatmentBMI >27 kg/m2 / BMI >30 kg/m2 / Type 2 Diabetes Mellitus1
4CompletedTreatmentHigh Blood Pressure (Hypertension) / Type 2 Diabetes Mellitus1
4CompletedTreatmentType 2 Diabetes Mellitus3
4Enrolling by InvitationBasic ScienceAcute Gouty Arthritis / Diabetes Mellitus (DM) / Hyperuricemia1
4RecruitingTreatmentBMI >30 kg/m2 / Type 2 Diabetes Mellitus1
4RecruitingTreatmentChronic Kidney Disease (CKD) / Type 2 Diabetes Mellitus1
4RecruitingTreatmentHeart Failure, Systolic / Type 2 Diabetes Mellitus1
4RecruitingTreatmentType 2 Diabetes Mellitus5
4RecruitingTreatmentType II Diabetes in Subjects BMI 27 to 32 / Type II Diabetes in the Not so Obese1
4WithdrawnBasic ScienceCardiovascular Disease (CVD) / Type2 Diabetes Mellitus1
4WithdrawnTreatmentDiabetes, Obesity1
Not AvailableActive Not RecruitingTreatmentDiabetes, Diabetes Mellitus Type 11
Not AvailableCompletedNot AvailableCardiovascular Disease (CVD) / Type 2 Diabetes Mellitus1
Not AvailableCompletedNot AvailableType 2 Diabetes Mellitus1
Not AvailableNot Yet RecruitingNot AvailableType 2 Diabetes Mellitus2
Not AvailableRecruitingTreatmentType 2 Diabetes Mellitus1
Not AvailableWithdrawnBasic ScienceHeart Failure, Unspecified / Type2 Diabetes1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Tablet, film coated, extended releaseOral
TabletOral100 mg
TabletOral300 mg
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral300 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6723340No2001-10-252021-10-25Us
US8222219No2004-07-302024-07-30Us
US8513202No2007-12-032027-12-03Us
US7943582No2009-02-262029-02-26Us
US8785403No2004-07-302024-07-30Us
US7943788No2007-07-142027-07-14Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0045 mg/mLALOGPS
logP3.09ALOGPS
logP3.52ChemAxon
logS-5ALOGPS
pKa (Strongest Acidic)12.57ChemAxon
pKa (Strongest Basic)-3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area90.15 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity116.14 m3·mol-1ChemAxon
Polarizability46.5 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9541
Blood Brain Barrier+0.7708
Caco-2 permeable-0.6554
P-glycoprotein substrateSubstrate0.6058
P-glycoprotein inhibitor INon-inhibitor0.8414
P-glycoprotein inhibitor IINon-inhibitor0.9447
Renal organic cation transporterNon-inhibitor0.8544
CYP450 2C9 substrateNon-substrate0.6853
CYP450 2D6 substrateNon-substrate0.8293
CYP450 3A4 substrateNon-substrate0.5929
CYP450 1A2 substrateNon-inhibitor0.6579
CYP450 2C9 inhibitorNon-inhibitor0.6178
CYP450 2D6 inhibitorNon-inhibitor0.8683
CYP450 2C19 inhibitorNon-inhibitor0.5958
CYP450 3A4 inhibitorNon-inhibitor0.7086
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7691
Ames testNon AMES toxic0.584
CarcinogenicityNon-carcinogens0.9103
BiodegradationNot ready biodegradable0.9936
Rat acute toxicity2.5975 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9912
hERG inhibition (predictor II)Non-inhibitor0.7246
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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 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
Hexoses / C-glycosyl compounds / Toluenes / Fluorobenzenes / 2,5-disubstituted thiophenes / Oxanes / Aryl fluorides / Heteroaromatic compounds / Secondary alcohols / Polyols
show 5 more
Substituents
Phenolic glycoside / Hexose monosaccharide / C-glycosyl compound / 2,5-disubstituted thiophene / Toluene / Fluorobenzene / Halobenzene / Aryl fluoride / Aryl halide / Monocyclic benzene moiety
show 17 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, thiophenes, ring assembly, C-glycosyl compound (CHEBI:73274)

Targets

Kind
Protein
Organism
Human
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. Lamos EM, Younk LM, Davis SN: Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin Drug Metab Toxicol. 2013 Jun;9(6):763-75. doi: 10.1517/17425255.2013.791282. Epub 2013 Apr 17. [PubMed:23590413]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Lamos EM, Younk LM, Davis SN: Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin Drug Metab Toxicol. 2013 Jun;9(6):763-75. doi: 10.1517/17425255.2013.791282. Epub 2013 Apr 17. [PubMed:23590413]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Sarnoski-Brocavich S, Hilas O: Canagliflozin (invokana), a novel oral agent for type-2 diabetes. P T. 2013 Nov;38(11):656-66. [PubMed:24391386]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGTs are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isozyme is active on polyhydroxylated estrogens (such as...
Gene Name
UGT2B4
Uniprot ID
P06133
Uniprot Name
UDP-glucuronosyltransferase 2B4
Molecular Weight
60512.035 Da
References
  1. Sarnoski-Brocavich S, Hilas O: Canagliflozin (invokana), a novel oral agent for type-2 diabetes. P T. 2013 Nov;38(11):656-66. [PubMed:24391386]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Lamos EM, Younk LM, Davis SN: Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin Drug Metab Toxicol. 2013 Jun;9(6):763-75. doi: 10.1517/17425255.2013.791282. Epub 2013 Apr 17. [PubMed:23590413]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
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

Drug created on June 17, 2013 00:21 / Updated on October 16, 2018 08:40