Identification

Summary

Indigotindisulfonic acid is a medication used to visualize ureteral orifices during cystoscopy and ureteral catheterization.

Generic Name
Indigotindisulfonic acid
DrugBank Accession Number
DB11577
Background

Indigotindisulfonic acid is a blue-colored dye with a variety of uses.2,3,4,12 Its salt form, indigotindisulfonate sodium, is also known as indigo carmine, indigotine or FD&C Blue #2. This compound is an acid-base indicator and is used in the production of food colorants and pH tests.7 Indigotindisulfonic acid is used in clinical medicine to determine patency of the urinary collecting system, and to assist in specific surgical procedures such as cystourethroscopy.2,3,4 In 2022, the FDA approved the intravenous use of indigotindisulfonate sodium to aid in visualizing ureter integrity in cystoscopic assessments.10

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 422.389
Monoisotopic: 421.987856686
Chemical Formula
C16H10N2O8S2
Synonyms
  • 2-(1,3-Dihydro-3-oxo-5-sulpho-2H-indol-2-ylidene)-3-oxoindoline-5-sulphonic acid
  • 5,5'-indigotindisulfonic Acid
  • Blue X
  • FD&C Blue #2
  • Indigo carmine
  • Indigo carmine acid
  • indigo carmine free acid
  • indigo-5,5'-disulfonic acid
  • Indigotindisulfonate
  • Indigotine
  • Saxon blue
External IDs
  • NSC-8646

Pharmacology

Indication

The main application of indigotindisulfonic acid is localizing and visualizing ureteral orifices during cystoscopy and ureteral catheterization procedures 9. Indigotindisulfonate sodium (salt form) is indicated for use as a visualization aid in the cystoscopic assessment of the integrity of the ureters in adults following urological and gynecological open, robotic, or endoscopic surgical procedures.10

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Approximately 4-9 minutes after indigotindisulfonate sodium is administered intravenously, its blue color is detectable at the ureteral orifices, enabling easier visualization for accuracy during medical procedures.10 Although indigotindisulfonic acid and its salt form indigotindisulfonate sodium were initially acknowledged as pharmacologically inert, their use has been associated with cardiovascular effects.1,2 Indigotindisulfonate sodium may lead to transient alpha-receptor stimulation, manifested as increased total peripheral vascular resistance, increased diastolic and systolic blood pressure, and increased central venous pressure with decreased cardiac output, stroke volume and heart rate.1 The use of indigotindisulfonate sodium may lead to severe or life-threatening cardiovascular reactions such as cardiac arrest, arrhythmia, asystole, second-degree atrioventricular block, hypotension, elevation in blood pressure, bradycardia, and tachycardia.10 Serious anaphylactic reactions with hypotension, dyspnea, bronchospasm, urticaria, or erythema have also been reported.10 Also, the use of indigotindisulfonate sodium may interfere with light absorption and pulse oximetric methods.10

Mechanism of action

Indigotindisulfonic acid is a biologically inert blue dye.5 After intravenous injection, indigotindisulfonic acid is excreted by the kidney through tubular secretion and, with its deep blue color, it enhances visualization of the ureteral orifices.10 Because of this, indigotindisulfonic acid is used to identify ureteral patency in urologic and gynecologic procedures.5

Indigotindisulfonic acid may lead to the development of hypertension. It has been suggested that indigotindisulfonic acid inhibits endothelium-dependent relaxation at the level of nitric oxide generation and/or its release from the endothelium. Also, indigotindisulfonic acid appears to inhibit vascular guanylyl cyclase in smooth muscle.2

TargetActionsOrganism
NAlpha adrenergic receptor
agonist
Humans
Absorption

In healthy adults given 5 ml of indigotindisulfonate sodium (salt form of indigotindisulfonic acid), the Cmax and AUC0-INF were 6.33 μg/mL and 1.15 μg·h/mL, respectively.10

Studies evaluating the pharmacokinetic properties of intravenous indigotindisulfonate sodium in patients with renal impairment have not been performed. Based on subgroup analyses in a randomized clinical trial, patients with mild to moderate renal impairment or an estimated glomerular filtration rate (eGFR) from 30 to 89 mL/min do not require dose adjustments. Indigotindisulfonate sodium is not recommended in patients with eGFR lower than 30 mL/min.10

Volume of distribution

The volume of distribution of indigotindisulfonate sodium is 10.7 L.10

Protein binding

The protein binding of indigotindisulfonate sodium in vitro is approximately 90%.10

Metabolism

Indigotindisulfonate sodium is mainly oxidized via primary metabolic pathways.10 An in vivo study done in rats showed that the breakdown of indigotindisulfonate sodium (FD&C Blue No. 2) generated two products: isatin-5-sulphonic acid and 5-sulphoanthranilic acid.6 Clinical studies evaluating indigotindisulfonate sodium metabolism products have not been performed.

Route of elimination

Indigotindisulfonic acid is excreted largely by the kidneys, retaining its blue color during passage through the body. Approximately 16% of the unchanged drug is excreted in urine, and less than 2% is excreted in feces.10 The elimination of this dye begins rapidly after injection, appearing in the urine within 5 minutes.8

Half-life

In healthy adults given 5 ml of indigotindisulfonate sodium, the elimination half-life was 12 minutes.10

Clearance

In healthy adults given 5 ml of indigotindisulfonate sodium, the mean urinary clearance was 7.08 L/hour, and the mean total clearance was 40.2 L/hour.10

Adverse Effects
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Toxicity

Toxicity information regarding indigotindisulfonic acid is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as cardiac arrest, arrhythmia, asystole, second degree atrioventricular block, hypotension, elevation in blood pressure, bradycardia, and tachycardia.10 Symptomatic and supportive measures are recommended.

The use of indigotindisulfonate sodium in pregnant women has not been associated with a higher risk of adverse maternal and fetal adverse effects. The use of this dye in the first trimester is rare; therefore, data are insufficient to evaluate the risk of major birth defects and miscarriage associated with the use of indigotindisulfonate sodium.10 It is not known whether this drug is excreted in human breastmilk. Fertility studies with indigotindisulfonate sodium using the intravenous route of administration have not been conducted.10

Carcinogenicity studies evaluating the effects of the intravenous administration of indigotindisulfonate sodium have not been performed. In mice, the long term subcutaneous administration of indigotindisulfonate sodium did not have carcinogenic effects.10 Indigotindisulfonate sodium was not genotoxic in Ames assays. The in vitro mutagenicity of this dye was inconclusive, and in vivo studies suggest that orally administered indigotindisulfonate was not mutagenic.10 The oral LD50 of indigotindisulfonate sodium in rats is 2000 mg/kg.11

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
AbacavirAbacavir may decrease the excretion rate of Indigotindisulfonic acid which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Indigotindisulfonic acid which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Indigotindisulfonic acid which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Indigotindisulfonic acid which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Indigotindisulfonic acid which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Indigotindisulfonic acid which could result in a higher serum level.
AclidiniumAclidinium may decrease the excretion rate of Indigotindisulfonic acid which could result in a higher serum level.
AcrivastineAcrivastine may decrease the excretion rate of Indigotindisulfonic acid which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Indigotindisulfonic acid which could result in a higher serum level.
Adefovir dipivoxilAdefovir dipivoxil may decrease the excretion rate of Indigotindisulfonic acid which could result in a higher serum level.
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Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Indigotindisulfonate sodiumD3741U8K7L860-22-0KHLVKKOJDHCJMG-QDBORUFSSA-L
International/Other Brands
Bludigo (Provepharm)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Indigo CarmineInjection, solution8 mg/1mLIntramuscular; IntravenousAkorn2009-04-012017-01-01US flag
Indigo CarmineInjection, solution8 mg/1mLIntramuscular; IntravenousA-S Medication Solutions1990-09-30Not applicableUS flag
Indigo CarmineSolution0.8 %Intramuscular; IntravenousAkorn Inc1994-12-312021-03-01Canada flag
Indigo CarmineInjection, solution8 mg/1mLIntramuscular; IntravenousAkorn2013-03-222017-01-01US flag
Indigo CarmineInjection, solution8 mg/1mLIntramuscular; IntravenousAMERICAN REGENT, INC.1990-09-30Not applicableUS flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Indigo CarmineIndigotindisulfonate sodium (8 mg/1mL)Injection, solutionIntramuscular; IntravenousAkorn2009-04-012017-01-01US flag
Indigo CarmineIndigotindisulfonate sodium (8 mg/1mL)Injection, solutionIntramuscular; IntravenousA-S Medication Solutions1990-09-30Not applicableUS flag
Indigo CarmineIndigotindisulfonate sodium (8 mg/1mL)Injection, solutionIntramuscular; IntravenousAkorn2013-03-222017-01-01US flag
Indigo CarmineIndigotindisulfonate sodium (8 mg/1mL)Injection, solutionIntramuscular; IntravenousAMERICAN REGENT, INC.1990-09-30Not applicableUS flag

Categories

ATC Codes
V04CH02 — Indigo carmine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as indolines. These are compounds containing an indole moiety, which consists of pyrrolidine ring fused to benzene to form 2,3-dihydroindole.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Indolines
Direct Parent
Indolines
Alternative Parents
1-sulfo,2-unsubstituted aromatic compounds / Aryl ketones / Secondary alkylarylamines / Benzenoids / Vinylogous amides / Sulfonyls / Organosulfonic acids / Enamines / Azacyclic compounds / Organopnictogen compounds
show 2 more
Substituents
1-sulfo,2-unsubstituted aromatic compound / Amine / Aromatic heteropolycyclic compound / Aryl ketone / Arylsulfonic acid or derivatives / Azacycle / Benzenoid / Dihydroindole / Enamine / Hydrocarbon derivative
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
X7OI7JF73P
CAS number
483-20-5
InChI Key
CFZXDJWFRVEWSR-BUHFOSPRSA-N
InChI
InChI=1S/C16H10N2O8S2/c19-15-9-5-7(27(21,22)23)1-3-11(9)17-13(15)14-16(20)10-6-8(28(24,25)26)2-4-12(10)18-14/h1-6,17-18H,(H,21,22,23)(H,24,25,26)/b14-13+
IUPAC Name
(E)-3,3'-dioxo-1H,1'H,3H,3'H-[2,2'-biindolylidene]-5,5'-disulfonic acid
SMILES
OS(=O)(=O)C1=CC2=C(N\C(C2=O)=C2\NC3=C(C=C(C=C3)S(O)(=O)=O)C2=O)C=C1

References

Synthesis Reference

Sayah, B., et al. (2020). Process for preparing indigo carmine (U.S. Patent No. 2020/0283632 A1). U.S. Patent and Trademark Office. Available at: https://patentimages.storage.googleapis.com/09/ec/73/46479d1a875d0e/US20200283632A1.pdf

General References
  1. Ng TY, Datta TD, Kirimli BI: Reaction to indigo carmine. J Urol. 1976 Jul;116(1):132-3. [Article]
  2. Chang KS, Zhong MZ, Davis RF: Indigo carmine inhibits endothelium-dependent and -independent vasodilation. Hypertension. 1996 Feb;27(2):228-34. [Article]
  3. Grimes CL, Patankar S, Ryntz T, Philip N, Simpson K, Truong M, Young C, Advincula A, Madueke-Laveaux OS, Walters R, Ananth CV, Kim JH: Evaluating ureteral patency in the post-indigo carmine era: a randomized controlled trial. Am J Obstet Gynecol. 2017 Nov;217(5):601.e1-601.e10. doi: 10.1016/j.ajog.2017.07.012. Epub 2017 Jul 18. [Article]
  4. Monson FC, Wein AJ, McKenna BA, Whitmore K, Levin RM: Indigocarmine as a quantitative indicator of urothelial integrity. J Urol. 1991 Apr;145(4):842-5. [Article]
  5. Kim SH, Suk EH, Kil SH, Hahm KD, Hwang JH: Hypotension in patients administered indigo carmine containing impurities -A case report-. Korean J Anesthesiol. 2011 Nov;61(5):435-8. doi: 10.4097/kjae.2011.61.5.435. Epub 2011 Nov 23. [Article]
  6. Lethco EJ, Webb JM: The fate of FD&C blue no. 2 in rats. J Pharmacol Exp Ther. 1966 Nov;154(2):384-9. [Article]
  7. Amchova P, Kotolova H, Ruda-Kucerova J: Health safety issues of synthetic food colorants. Regul Toxicol Pharmacol. 2015 Dec;73(3):914-22. doi: 10.1016/j.yrtph.2015.09.026. Epub 2015 Sep 25. [Article]
  8. Deture FA, Drylie DM: Evaluation of indigo carmine as an indicator of renal function. J Urol. 1974 Dec;112(6):693-6. doi: 10.1016/s0022-5347(17)59830-4. [Article]
  9. Indigo Carmine Daily Med [Link]
  10. FDA Approved Drug Products: BLUDIGO (indigotindisulfonate sodium) injection for intravenous use [Link]
  11. Alphachem: Indigo carmine SDS [Link]
  12. European Food Safety Authority: Scientific Opinion on the re-evaluation of Indigo Carmine (E 132) as a food additive [Link]
Human Metabolome Database
HMDB0059912
PubChem Compound
5282430
PubChem Substance
347827990
ChemSpider
4445584
RxNav
325514
ChEBI
90117
ChEMBL
CHEMBL1091250
ZINC
ZINC000100005073
Wikipedia
Indigo_carmine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentNeoplasms, Colorectal1
2SuspendedTreatmentAD / Aging / Alzheimer's Disease (AD) / MCI / Mild Cognitive Impairment (MCI)1
1CompletedDiagnosticColorectal Adenomas1
1, 2CompletedTreatmentBrain Tumors With Ill-defined Margins1
0CompletedBasic ScienceBrain Activity1
Not AvailableUnknown StatusDiagnosticInflammatory Bowel Diseases (IBD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntramuscular; Intravenous8 mg/1mL
SolutionIntramuscular; Intravenous0.8 %
InjectionIntramuscular; Intravenous4 mg/mL
Injection, solutionUreteral
Injection, solutionIntravenous40 MG/10ML
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)>300SDS
water solubility0.1-1g/100ml SDS
Predicted Properties
PropertyValueSource
Water Solubility0.0996 mg/mLALOGPS
logP-0.94ALOGPS
logP1.01ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)-2.8ChemAxon
pKa (Strongest Basic)-7.7ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area166.94 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity101.29 m3·mol-1ChemAxon
Polarizability39.65 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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

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Kind
Protein group
Organism
Humans
Pharmacological action
No
Actions
Agonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...

Components:
References
  1. Kim SH, Suk EH, Kil SH, Hahm KD, Hwang JH: Hypotension in patients administered indigo carmine containing impurities -A case report-. Korean J Anesthesiol. 2011 Nov;61(5):435-8. doi: 10.4097/kjae.2011.61.5.435. Epub 2011 Nov 23. [Article]

Drug created at April 12, 2016 03:24 / Updated at August 12, 2022 17:06