Identification

Name
Bendroflumethiazide
Accession Number
DB00436  (APRD00666)
Type
Small Molecule
Groups
Approved
Description

A thiazide diuretic with actions and uses similar to those of hydrochlorothiazide. It has been used in the treatment of familial hyperkalemia, hypertension, edema, and urinary tract disorders. (From Martindale, The Extra Pharmacopoeia, 30th ed, p810)

Structure
Thumb
Synonyms
  • +--3-Benzyl-3,4-dihydro-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide
  • 6-Trifluoromethyl-3-benzyl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide
  • Bendrofluazide
  • Bendroflumethiazid
  • Bendrofluméthiazide
  • Bendroflumethiazidum
  • Bendroflumetiazida
  • Benzhydroflumethiazide
External IDs
BE 724-A / FT 81
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NaturetinTablet5 mg/1OralE.R. Squibb & Sons, L.L.C.2005-01-012006-10-31Us
Naturetin 5mgTablet5 mgOralSquibb Canada Inc., Division Of Bristol Myers Squibb Canada Inc.1959-12-311999-01-07Canada
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
CorzideBendroflumethiazide (5 mg/1) + Nadolol (80 mg/1)TabletOralPfizer Laboratories Div Pfizer Inc.1983-05-25Not applicableUs
CorzideBendroflumethiazide (5 mg/1) + Nadolol (80 mg/1)TabletOralPhysicians Total Care, Inc.1983-05-252010-06-30Us
CorzideBendroflumethiazide (5 mg/1) + Nadolol (80 mg/1)TabletOralMonarch Pharmaceuticals, Inc.2006-10-102006-10-10Us
CorzideBendroflumethiazide (5 mg/1) + Nadolol (40 mg/1)TabletOralPfizer Laboratories Div Pfizer Inc.1983-05-25Not applicableUs
CorzideBendroflumethiazide (5 mg/1) + Nadolol (40 mg/1)TabletOralMonarch Pharmaceuticals, Inc.2006-10-102006-10-10Us
Corzide Tab W Nadolol 40mgBendroflumethiazide (5 mg) + Nadolol (40 mg)TabletOralSquibb Canada Inc., Division Of Bristol Myers Squibb Canada Inc.1987-12-311997-08-14Canada
Corzide Tab W Nadolol 80mgBendroflumethiazide (5 mg) + Nadolol (80 mg)TabletOralSquibb Canada Inc., Division Of Bristol Myers Squibb Canada Inc.1987-12-311997-08-14Canada
Nadolol and BendroflumethiazideBendroflumethiazide (5 mg/1) + Nadolol (40 mg/1)TabletOralMylan Pharmaceuticals2012-04-022012-08-31Us
Nadolol and BendroflumethiazideBendroflumethiazide (5 mg/1) + Nadolol (40 mg/1)TabletOralImpax Generics2007-03-30Not applicableUs
Nadolol and BendroflumethiazideBendroflumethiazide (5 mg/1) + Nadolol (80 mg/1)TabletOralMylan Pharmaceuticals2012-04-022012-08-31Us
International/Other Brands
Aprinox (Sovereign Medical) / Centyl (LEO Pharma) / Naturetin / Neo-Naclex (GlaxoSmithKline) / Salures (Pfizer)
Categories
UNII
5Q52X6ICJI
CAS number
73-48-3
Weight
Average: 421.415
Monoisotopic: 421.037781946
Chemical Formula
C15H14F3N3O4S2
InChI Key
HDWIHXWEUNVBIY-UHFFFAOYSA-N
InChI
InChI=1S/C15H14F3N3O4S2/c16-15(17,18)10-7-11-13(8-12(10)26(19,22)23)27(24,25)21-14(20-11)6-9-4-2-1-3-5-9/h1-5,7-8,14,20-21H,6H2,(H2,19,22,23)
IUPAC Name
3-benzyl-1,1-dioxo-6-(trifluoromethyl)-3,4-dihydro-2H-1λ⁶,2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=CC2=C(NC(CC3=CC=CC=C3)NS2(=O)=O)C=C1C(F)(F)F

Pharmacology

Indication

For the treatment of high blood pressure and management of edema related to heart failure.

Associated Conditions
Pharmacodynamics

Bendroflumethiazide, a thiazide diuretic, removes excess water from the body by increasing how often you urinate (pass water) and also widens the blood vessels which helps to reduce blood pressure. It inhibits Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue.

Mechanism of action

As a diuretic, bendroflumethiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like bendroflumethiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of bendroflumethiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle.

TargetActionsOrganism
ASolute carrier family 12 member 3
inhibitor
Human
ACalcium-activated potassium channel subunit alpha-1
inducer
Human
UCarbonic anhydrase 1
inhibitor
Human
UCarbonic anhydrase 2
inhibitor
Human
UCarbonic anhydrase 4
inhibitor
Human
Absorption

Absorbed relatively rapidly after oral administration

Volume of distribution
Not Available
Protein binding

96%

Metabolism
Not Available
Route of elimination
Not Available
Half life

8.5 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Bendroflumethiazide Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
1alpha-Hydroxyvitamin D5The risk or severity of hypercalcemia can be increased when Bendroflumethiazide is combined with 1alpha-Hydroxyvitamin D5.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Bendroflumethiazide.
AbediterolAbediterol may increase the hypokalemic activities of Bendroflumethiazide.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Bendroflumethiazide.
AcebutololThe risk or severity of adverse effects can be increased when Bendroflumethiazide is combined with Acebutolol.
AceclofenacThe therapeutic efficacy of Bendroflumethiazide can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Bendroflumethiazide can be decreased when used in combination with Acemetacin.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Bendroflumethiazide.
AcetyldigitoxinThe risk or severity of adverse effects can be increased when Bendroflumethiazide is combined with Acetyldigitoxin.
AcetyldigoxinThe risk or severity of adverse effects can be increased when Bendroflumethiazide is combined with Acetyldigoxin.
Food Interactions
  • Take with food to increase bioavailability.

References

Synthesis Reference

Goldberg, M.; U.S. Patent 3,265,573; August 9, 1966; assigned to E.R. Squibb & Sons, Inc. Lund, F., Lyngby, K. and Godtfredsen, W.O.; U.S. Patent 3,392,168; July 9, 1968; assigned to Lovens Kemiske Fabrik ved A. Kongsted, Denmark.

General References
Not Available
External Links
Human Metabolome Database
HMDB0014580
KEGG Drug
D00650
KEGG Compound
C07758
PubChem Compound
2315
PubChem Substance
46508672
ChemSpider
2225
ChEBI
3013
ChEMBL
CHEMBL1684
Therapeutic Targets Database
DAP000188
PharmGKB
PA448563
Drugs.com
Drugs.com Drug Page
Wikipedia
Bendroflumethiazide
ATC Codes
C03AA01 — BendroflumethiazideC03EA13 — Bendroflumethiazide and potassium-sparing agentsC03AB01 — Bendroflumethiazide and potassiumG01AE10 — Combinations of sulfonamides
MSDS
Download (72.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers2
4CompletedTreatmentHigh Blood Pressure (Hypertension)1

Pharmacoeconomics

Manufacturers
  • Apothecon inc div bristol myers squibb
Packagers
  • E.R. Squibb and Sons LLC
  • King Pharmaceuticals Inc.
  • Physicians Total Care Inc.
  • Professional Co.
Dosage forms
FormRouteStrength
TabletOral
TabletOral5 mg/1
TabletOral5 mg
Prices
Unit descriptionCostUnit
Bendroflumethiazide powder45.0USD g
Corzide 80-5 tablet4.29USD tablet
Corzide 40-5 mg tablet3.46USD tablet
Corzide 40-5 tablet3.35USD tablet
Corzide 80-5 mg tablet3.23USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)222-223 °CGoldberg, M.; U.S. Patent 3,265,573; August 9, 1966; assigned to E.R. Squibb & Sons, Inc. Lund, F., Lyngby, K. and Godtfredsen, W.O.; U.S. Patent 3,392,168; July 9, 1968; assigned to Lovens Kemiske Fabrik ved A. Kongsted, Denmark.
water solubility108 mg/L (at 25 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP1.89BERTHOD,A ET AL. (1999)
logS-3.59ADME Research, USCD
pKa8.5SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.214 mg/mLALOGPS
logP1.83ALOGPS
logP1.7ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)9.04ChemAxon
pKa (Strongest Basic)-3.1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area118.36 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity93.68 m3·mol-1ChemAxon
Polarizability36.92 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9643
Blood Brain Barrier-0.7807
Caco-2 permeable-0.7105
P-glycoprotein substrateNon-substrate0.6048
P-glycoprotein inhibitor INon-inhibitor0.7889
P-glycoprotein inhibitor IINon-inhibitor0.8383
Renal organic cation transporterNon-inhibitor0.8835
CYP450 2C9 substrateNon-substrate0.708
CYP450 2D6 substrateNon-substrate0.8398
CYP450 3A4 substrateNon-substrate0.6596
CYP450 1A2 substrateInhibitor0.8745
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.9351
CYP450 2C19 inhibitorNon-inhibitor0.9287
CYP450 3A4 inhibitorNon-inhibitor0.8607
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9081
Ames testNon AMES toxic0.8474
CarcinogenicityNon-carcinogens0.8156
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.0888 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9858
hERG inhibition (predictor II)Non-inhibitor0.8967
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 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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00di-0353900000-1c8856fba9af1de07f87
MS/MS Spectrum - , positiveLC-MS/MSsplash10-044i-3891000000-67bb3f0457a6200bf63e

Taxonomy

Description
This compound belongs to the class of organic compounds known as 1,2,4-benzothiadiazine-1,1-dioxides. These are aromatic heterocyclic compounds containing a 1,2,4-benzothiadiazine ring system with two S=O bonds at the 1-position.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Thiadiazines
Sub Class
Benzothiadiazines
Direct Parent
1,2,4-benzothiadiazine-1,1-dioxides
Alternative Parents
Secondary alkylarylamines / Organosulfonamides / Benzene and substituted derivatives / Aminosulfonyl compounds / Azacyclic compounds / Organopnictogen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives / Alkyl fluorides
Substituents
1,2,4-benzothiadiazine-1,1-dioxide / Secondary aliphatic/aromatic amine / Monocyclic benzene moiety / Benzenoid / Organosulfonic acid amide / Organic sulfonic acid or derivatives / Organosulfonic acid or derivatives / Aminosulfonyl compound / Sulfonyl / Secondary amine
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
sulfonamide, benzothiadiazine (CHEBI:3013)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transporter activity
Specific Function
Key mediator of sodium and chloride reabsorption in this nephron segment, accounting for a significant fraction of renal sodium reabsorption.
Gene Name
SLC12A3
Uniprot ID
P55017
Uniprot Name
Solute carrier family 12 member 3
Molecular Weight
113138.04 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Monroy A, Plata C, Hebert SC, Gamba G: Characterization of the thiazide-sensitive Na(+)-Cl(-) cotransporter: a new model for ions and diuretics interaction. Am J Physiol Renal Physiol. 2000 Jul;279(1):F161-9. [PubMed:10894798]
  3. Vallon V, Rieg T, Ahn SY, Wu W, Eraly SA, Nigam SK: Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am J Physiol Renal Physiol. 2008 Apr;294(4):F867-73. doi: 10.1152/ajprenal.00528.2007. Epub 2008 Jan 23. [PubMed:18216144]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inducer
General Function
Voltage-gated potassium channel activity
Specific Function
Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also activated by the concentration of cytosolic Mg(2+). Its activati...
Gene Name
KCNMA1
Uniprot ID
Q12791
Uniprot Name
Calcium-activated potassium channel subunit alpha-1
Molecular Weight
137558.115 Da
References
  1. Tricarico D, Barbieri M, Mele A, Carbonara G, Camerino DC: Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats. FASEB J. 2004 Apr;18(6):760-1. Epub 2004 Feb 6. [PubMed:14766795]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea.
Gene Name
CA1
Uniprot ID
P00915
Uniprot Name
Carbonic anhydrase 1
Molecular Weight
28870.0 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion in...
Gene Name
CA2
Uniprot ID
P00918
Uniprot Name
Carbonic anhydrase 2
Molecular Weight
29245.895 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina an...
Gene Name
CA4
Uniprot ID
P22748
Uniprot Name
Carbonic anhydrase 4
Molecular Weight
35032.075 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Thiopurine s-methyltransferase activity
Specific Function
Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine.
Gene Name
TPMT
Uniprot ID
P51580
Uniprot Name
Thiopurine S-methyltransferase
Molecular Weight
28180.09 Da
References
  1. Lysaa RA, Giverhaug T, Wold HL, Aarbakke J: Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide. Eur J Clin Pharmacol. 1996;49(5):393-6. [PubMed:8866635]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:43