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Identification
NameMetolazone
Accession NumberDB00524  (APRD01109)
Typesmall molecule
Groupsapproved
Description

A quinazoline-sulfonamide that is considered a thiazide-like diuretic which is long-acting so useful in chronic renal failure. It also tends to lower blood pressure and increase potassium loss. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
2-Methyl-3-O-tolyl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinoneNot AvailableNot Available
7-Chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamideNot AvailableNot Available
7-Chloro-1,2,3,4-tetrahydro-2-methyl-4-oxo-3-O-tolyl-6-quinazolinesulfonamideNot AvailableNot Available
MetolazonGermanINN
MetolazonaSpanishINN
MétolazoneFrenchINN
MetolazonumLatinINN
ZaroxolynNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
DiuloNot Available
DiuremCipla
MetadureMicro Labs
MetenixIFET
MetolazNavana
MetolazoneSandoz
MetoralDr. Reddy's
MetozCentaur
MetozoneYing Yuan
MykroxCelltech
PavedalPharma Investi
Zaroxolynsanofi-aventis
ZytanixZydus
Brand mixturesNot Available
Categories
CAS number17560-51-9
WeightAverage: 365.835
Monoisotopic: 365.06008979
Chemical FormulaC16H16ClN3O3S
InChI KeyAQCHWTWZEMGIFD-UHFFFAOYSA-N
InChI
InChI=1S/C16H16ClN3O3S/c1-9-5-3-4-6-14(9)20-10(2)19-13-8-12(17)15(24(18,22)23)7-11(13)16(20)21/h3-8,10,19H,1-2H3,(H2,18,22,23)
IUPAC Name
7-chloro-2-methyl-3-(2-methylphenyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide
SMILES
CC1NC2=CC(Cl)=C(C=C2C(=O)N1C1=CC=CC=C1C)S(N)(=O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassNaphthyridines
SubclassQuinazolines
Direct parentQuinazolines
Alternative parentsBenzenesulfonamides; Toluenes; Chlorobenzenes; Aryl Chlorides; Sulfonamides; Tertiary Carboxylic Acid Amides; Sulfonyls; Tertiary Amines; Polyamines; Carboxylic Acids; Secondary Amines; Organochlorides
Substituentschlorobenzene; toluene; aryl chloride; aryl halide; benzene; sulfonic acid derivative; sulfonamide; tertiary carboxylic acid amide; sulfonyl; tertiary amine; carboxamide group; carboxylic acid derivative; polyamine; carboxylic acid; secondary amine; organochloride; organohalogen; amine; organonitrogen compound
Classification descriptionThis compound belongs to the quinazolines. These are compounds containing a quinazoline moiety, which is made up of two fused six-member aromatic rings, a benzene ring and a pyrimidine ring.
Pharmacology
IndicationFor the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class.
PharmacodynamicsMetolazone is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. A proximal action of metolazone has been shown in humans by increased excretion of phosphate and magnesium ions and by a markedly increased fractional excretion of sodium in patients with severely compromised glomerular filtration. This action has been demonstrated in animals by micropuncture studies.
Mechanism of actionThe actions of metolazone result from interference with the renal tubular mechanism of electrolyte reabsorption. Metolazone acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalent amounts. The increased delivery of sodium to the distal tubular exchange site results in increased potassium excretion. Metolazone does not inhibit carbonic anhydrase. The antihypertensive mechanism of action of metolazone is not fully understood but is presumed to be related to its saluretic and diuretic properties.
AbsorptionPeak blood levels are obtained within 2 to 4 hours of oral administration. The rate and extent of absorption are formulation dependent.
Volume of distributionNot Available
Protein binding50-70% bound to erythrocytes, up to 33% bound to plasma proteins, 2-5% of the drug in circulation is unbound
Metabolism

Not substantially metabolized. 70-95% is excreted unchanged in urine via glomerular filtration and active tubular secretion. Undergoes enterohepatic recycling.

Route of eliminationMost of the drug is excreted in the unconverted form in the urine.
Half lifeApproximately 14 hours.
ClearanceNot Available
ToxicitySymptoms of overdose include difficulty breathing, dizziness, dizziness on standing up, drowsiness, fainting, irritation of the stomach and intestines, and lethargy leading to coma.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Metolazone Action PathwayDrug actionSMP00105
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9972
Blood Brain Barrier + 0.5944
Caco-2 permeable - 0.8957
P-glycoprotein substrate Non-substrate 0.7578
P-glycoprotein inhibitor I Non-inhibitor 0.8113
P-glycoprotein inhibitor II Non-inhibitor 0.5921
Renal organic cation transporter Non-inhibitor 0.9223
CYP450 2C9 substrate Non-substrate 0.6466
CYP450 2D6 substrate Non-substrate 0.8279
CYP450 3A4 substrate Non-substrate 0.579
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.907
CYP450 2D6 substrate Non-inhibitor 0.923
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.831
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5788
Ames test Non AMES toxic 0.8234
Carcinogenicity Non-carcinogens 0.7193
Biodegradation Not ready biodegradable 0.9961
Rat acute toxicity 1.8955 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9922
hERG inhibition (predictor II) Non-inhibitor 0.8735
Pharmacoeconomics
Manufacturers
  • Gd searle llc
  • Mylan pharmaceuticals inc
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • Ucb inc
Packagers
Dosage forms
FormRouteStrength
TabletOral10 mg
TabletOral2.5 mg
TabletOral5 mg
Prices
Unit descriptionCostUnit
Zaroxolyn 10 mg tablet2.89USDtablet
Zaroxolyn 5 mg tablet2.75USDtablet
Metolazone 10 mg tablet1.8USDtablet
Zaroxolyn 2.5 mg tablet1.74USDtablet
Metolazone 5 mg tablet1.51USDtablet
Metolazone 2.5 mg tablet1.37USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point256 °CPhysProp
water solubility60.3 mg/L (at 25 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP2.5Not Available
logS-3.78ADME Research, USCD
Predicted Properties
PropertyValueSource
water solubility4.07e-02 g/lALOGPS
logP3.21ALOGPS
logP2.94ChemAxon
logS-4ALOGPS
pKa (strongest acidic)9.54ChemAxon
pKa (strongest basic)-1.6ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count2ChemAxon
polar surface area92.5ChemAxon
rotatable bond count2ChemAxon
refractivity94.59ChemAxon
polarizability36.38ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Rosenberg J, Gustafsson F, Galatius S, Hildebrandt PR: Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature. Cardiovasc Drugs Ther. 2005 Aug;19(4):301-6. Pubmed
External Links
ResourceLink
KEGG DrugD00431
PubChem Compound4170
PubChem Substance46509058
ChemSpider4026
BindingDB25899
Therapeutic Targets DatabaseDAP000749
PharmGKBPA164781022
Drug Product Database888400
RxListhttp://www.rxlist.com/cgi/generic2/metolazone.htm
Drugs.comhttp://www.drugs.com/cdi/metolazone.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/zar1495.shtml
WikipediaMetolazone
ATC CodesC03BA08
AHFS Codes
  • 40:28.24
PDB EntriesNot Available
FDA labelshow(834 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
DeslanosidePossible electrolyte variations and arrhythmias
DigitoxinPossible electrolyte variations and arrhythmias
DigoxinPossible electrolyte variations and arrhythmias
DofetilideIncreased risk of cardiotoxicity and arrhythmias
LithiumThe thiazide diuretic, metolazone, may increase serum levels of lithium.
TenoxicamTenoxicam may antagonize the blood pressure lowering effect of Metolazone. Monitor for changes in the therapeutic effect of Metolazone if Tenoxicam is initiated, discontinued or dose changed.
TrandolaprilThe thiazide diuretic, Metolazone, may increase the hypotensive effect of Trandolapril. Metolazone 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 reduce gastric irritation.

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

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Drug created on June 13, 2005 07:24 / Updated on February 04, 2014 21:27