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Identification
NameBendroflumethiazide
Accession NumberDB00436  (APRD00666)
TypeSmall Molecule
GroupsApproved
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
SynonymLanguageCode
+--3-Benzyl-3,4-dihydro-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxideNot AvailableNot Available
6-Trifluoromethyl-3-benzyl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxideNot AvailableNot Available
BendrofluazideNot AvailableIS
BendroflumethiazidGermanINN
BendrofluméthiazideFrenchINN
BendroflumethiazidumLatinINN
BendroflumetiazidaSpanishINN
BenzhydroflumethiazideNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AprinoxSovereign Medical
CentylLEO Pharma
NaturetinNot Available
Neo-NaclexGlaxoSmithKline
SaluresPfizer
Brand mixtures
Brand NameIngredients
CorzideBendroflumethiazide + Nadolol
Neo-Naclex-KBendroflumethiazide and Potassium Chloride
PrestimBendroflumethiazide and Timolol
RauzideBendroflumethiazide + Rauwolfia serpentina
TensionormeBendroflumethiazide and Reserpine
TensofluxBendroflumethiazide and Amiloride
Categories
CAS number73-48-3
WeightAverage: 421.415
Monoisotopic: 421.037781946
Chemical FormulaC15H14F3N3O4S2
InChI KeyHDWIHXWEUNVBIY-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-1$l^{6},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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassThiadiazines
SubclassBenzothiadiazines
Direct parentBenzothiadiazines
Alternative parentsBenzenesulfonamides; Sulfonamides; Sulfonyls; Polyamines; Secondary Amines; Organofluorides; Alkyl Fluorides
Substituentsbenzene; sulfonyl; sulfonic acid derivative; sulfonamide; secondary amine; polyamine; organonitrogen compound; amine; organofluoride; organohalogen; alkyl halide; alkyl fluoride
Classification descriptionThis compound belongs to the benzothiadiazines. These are organic compounds containing a benzene fused to a thiadiazine ring (a six-member ring with two nitrogen atoms and a sulfur atom).
Pharmacology
IndicationFor the treatment of high blood pressure and management of edema related to heart failure.
PharmacodynamicsBendroflumethiazide, 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 actionAs 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.
AbsorptionAbsorbed relatively rapidly after oral administration
Volume of distributionNot Available
Protein binding96%
Metabolism
Route of eliminationNot Available
Half life8.5 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Bendroflumethiazide Action PathwayDrug actionSMP00090
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9643
Blood Brain Barrier - 0.7807
Caco-2 permeable - 0.7105
P-glycoprotein substrate Non-substrate 0.6048
P-glycoprotein inhibitor I Non-inhibitor 0.7889
P-glycoprotein inhibitor II Non-inhibitor 0.8383
Renal organic cation transporter Non-inhibitor 0.8835
CYP450 2C9 substrate Non-substrate 0.708
CYP450 2D6 substrate Non-substrate 0.8398
CYP450 3A4 substrate Non-substrate 0.6596
CYP450 1A2 substrate Inhibitor 0.8745
CYP450 2C9 substrate Non-inhibitor 0.907
CYP450 2D6 substrate Non-inhibitor 0.9351
CYP450 2C19 substrate Non-inhibitor 0.9287
CYP450 3A4 substrate Non-inhibitor 0.8607
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9081
Ames test Non AMES toxic 0.8474
Carcinogenicity Non-carcinogens 0.8156
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.0888 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9858
hERG inhibition (predictor II) Non-inhibitor 0.8967
Pharmacoeconomics
Manufacturers
  • Apothecon inc div bristol myers squibb
Packagers
Dosage formsNot Available
Prices
Unit descriptionCostUnit
Bendroflumethiazide powder45.0USDg
Corzide 80-5 tablet4.29USDtablet
Corzide 40-5 mg tablet3.46USDtablet
Corzide 40-5 tablet3.35USDtablet
Corzide 80-5 mg tablet3.23USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point222-223 °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 Solubility0.214ALOGPS
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
Spectra
SpectraNot Available
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 ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00650
KEGG CompoundC07758
PubChem Compound2315
PubChem Substance46508672
ChemSpider2225
ChEBI3013
ChEMBLCHEMBL1684
Therapeutic Targets DatabaseDAP000188
PharmGKBPA448563
Drug Product Database29343
Drugs.comhttp://www.drugs.com/cdi/bendroflumethiazide.html
WikipediaBendroflumethiazide
ATC CodesC03AA01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(72.8 KB)
Interactions
Drug Interactions
Drug
DeslanosidePossible electrolyte variations and arrhythmias
DiazoxideSignificant hyperglycemic effect
DigitoxinPossible electrolyte variations and arrhythmias
DigoxinPossible electrolyte variations and arrhythmias
DofetilideIncreased risk of cardiotoxicity and arrhythmias
LithiumThe thiazide diuretic, bendroflumethiazide, may increase serum levels of lithium.
TrandolaprilThe thiazide diuretic, Bendroflumethiazide, may increase the hypotensive effect of Trandolapril. Bendroflumethiazide may also increase the nephrotoxicity of Trandolapril. Monitor for postural hypotension at initiation of concomitant therapy and renal dysfunction during chronic therapy.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food Interactions
  • Take with food to increase bioavailability.

Targets

1. Solute carrier family 12 member 3

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 12 member 3 P55017 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  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
  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. Epub 2008 Jan 23. Pubmed

2. Calcium-activated potassium channel subunit alpha-1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inducer

Components

Name UniProt ID Details
Calcium-activated potassium channel subunit alpha-1 Q12791 Details

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

3. Carbonic anhydrase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 1 P00915 Details

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
  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

4. Carbonic anhydrase 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 2 P00918 Details

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
  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

5. Carbonic anhydrase 4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 4 P22748 Details

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
  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

Enzymes

1. Thiopurine S-methyltransferase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Thiopurine S-methyltransferase P51580 Details

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

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Drug created on June 13, 2005 07:24 / Updated on March 31, 2014 13:39