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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
2-Methyl-3-O-tolyl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone
7-Chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamide
7-Chloro-1,2,3,4-tetrahydro-2-methyl-4-oxo-3-O-tolyl-6-quinazolinesulfonamide
Metolazon
Metolazona
Métolazone
Metolazonum
Zaroxolyn
External Identifiers
  • SR 720-22
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Metolazonetablet10 mg/1oralUpstate Pharma, LLC1973-11-27Not applicableUs
Metolazonetablet5 mg/1oralUpstate Pharma, LLC1973-11-27Not applicableUs
Metolazonetablet2.5 mg/1oralAvera Mc Kennan Hospital2015-04-16Not applicableUs
Metolazonetablet2.5 mg/1oralUpstate Pharma, LLC1973-11-27Not applicableUs
Zaroxolyntablet5 mg/1oralUNITHER Manufacturing LLC1973-11-272016-01-13Us
Zaroxolyntablet5 mgoralAventis Pharma Inc1974-12-312003-07-22Canada
Zaroxolyntablet2.5 mgoralSanofi Aventis Canada Inc1974-12-31Not applicableCanada
Zaroxolyntablet2.5 mg/1oralCarilion Materials Management1973-11-27Not applicableUs
Zaroxolyn Tab 10mgtablet10 mgoralRhone Poulenc Rorer Canada Inc.1974-12-311998-08-12Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Metolazonetablet2.5 mg/1oralPhysicians Total Care, Inc.2004-07-06Not applicableUs
Metolazonetablet5 mg/1oralEon Labs, Inc.2003-12-19Not applicableUs
Metolazonetablet2.5 mg/1oralCardinal Health2011-01-14Not applicableUs
Metolazonetablet2.5 mg/1oralNcs Health Care Of Ky, Inc Dba Vangard Labs2003-12-19Not applicableUs
Metolazonetablet5 mg/1oralPhysicians Total Care, Inc.2004-04-27Not applicableUs
Metolazonetablet10 mg/1oralMylan Pharmaceuticals Inc.2004-10-19Not applicableUs
Metolazonetablet5 mg/1oralMylan Institutional Inc.2005-02-01Not applicableUs
Metolazonetablet5 mg/1oralMylan Pharmaceuticals Inc.2004-10-19Not applicableUs
Metolazonetablet2.5 mg/1oralMylan Institutional Inc.2005-04-15Not applicableUs
Metolazonetablet10 mg/1oralCarilion Materials Management2004-10-19Not applicableUs
Metolazonetablet2.5 mg/1oralMylan Pharmaceuticals Inc.2004-01-06Not applicableUs
Metolazonetablet5 mg/1oralNcs Health Care Of Ky, Inc Dba Vangard Labs2010-01-18Not applicableUs
Metolazonetablet10 mg/1oralEon Labs, Inc.2003-12-19Not applicableUs
Metolazonetablet5 mg/1oralMc Kesson Packaging Services A Business Unit Of Mc Kesson Corporation2006-11-15Not applicableUs
Metolazonetablet2.5 mg/1oralNcs Health Care Of Ky, Inc Dba Vangard Labs2010-01-18Not applicableUs
Metolazonetablet10 mg/1oralPhysicians Total Care, Inc.2004-07-20Not applicableUs
Metolazonetablet2.5 mg/1oralEon Labs, Inc.2003-12-19Not applicableUs
Metolazonetablet5 mg/1oralCardinal Health2011-01-14Not applicableUs
Metolazonetablet5 mg/1oralNcs Health Care Of Ky, Inc Dba Vangard Labs2003-12-19Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
DiuloNot Available
DiuremCipla
MetadureMicro Labs
MetenixIFET
MetolazNavana
MetoralDr. Reddy's
MetozCentaur
MetozoneYing Yuan
MykroxCelltech
PavedalPharma Investi
ZytanixZydus
Brand mixturesNot Available
SaltsNot Available
Categories
UNIITZ7V40X7VX
CAS number17560-51-9
WeightAverage: 365.835
Monoisotopic: 365.06008979
Chemical FormulaC16H16ClN3O3S
InChI KeyInChIKey=AQCHWTWZEMGIFD-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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassNaphthyridines
Sub ClassQuinazolines
Direct ParentQuinazolines
Alternative Parents
Substituents
  • Quinazoline
  • Aminotoluene
  • Toluene
  • Secondary aliphatic/aromatic amine
  • Benzenoid
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl chloride
  • Vinylogous amide
  • Aminosulfonyl compound
  • Sulfonyl
  • Sulfonic acid derivative
  • Sulfonamide
  • Tertiary amine
  • Lactam
  • Carboxamide group
  • Azacycle
  • Secondary amine
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
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.
Related Articles
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
PropertyValueProbability
Human Intestinal Absorption+0.9972
Blood Brain Barrier+0.5944
Caco-2 permeable-0.8957
P-glycoprotein substrateNon-substrate0.7578
P-glycoprotein inhibitor INon-inhibitor0.8113
P-glycoprotein inhibitor IINon-inhibitor0.5921
Renal organic cation transporterNon-inhibitor0.9223
CYP450 2C9 substrateNon-substrate0.6466
CYP450 2D6 substrateNon-substrate0.8279
CYP450 3A4 substrateNon-substrate0.579
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.923
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.831
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5788
Ames testNon AMES toxic0.8234
CarcinogenicityNon-carcinogens0.7193
BiodegradationNot ready biodegradable0.9961
Rat acute toxicity1.8955 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9922
hERG inhibition (predictor II)Non-inhibitor0.8735
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
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/1
Tabletoral2.5 mg/1
Tabletoral5 mg/1
Tabletoral2.5 mg
Tabletoral5 mg
Tabletoral10 mg
Prices
Unit descriptionCostUnit
Zaroxolyn 10 mg tablet2.89USD tablet
Zaroxolyn 5 mg tablet2.75USD tablet
Metolazone 10 mg tablet1.8USD tablet
Zaroxolyn 2.5 mg tablet1.74USD tablet
Metolazone 5 mg tablet1.51USD tablet
Metolazone 2.5 mg tablet1.37USD tablet
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 Solubility0.0407 mg/mLALOGPS
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 Area92.5 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity94.59 m3·mol-1ChemAxon
Polarizability36.38 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  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:16189620 ]
External Links
ATC CodesC03BA08C03EA12
AHFS Codes
  • 40:28.24
PDB EntriesNot Available
FDA labelDownload (834 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Metolazone.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Acetylsalicylic acid is combined with Metolazone.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Metolazone.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Metolazone.
AlfuzosinAlfuzosin may increase the hypotensive activities of Metolazone.
AllopurinolThe risk of a hypersensitivity reaction to Allopurinol is increased when it is combined with Metolazone.
AlogliptinThe therapeutic efficacy of Alogliptin can be decreased when used in combination with Metolazone.
AmifostineMetolazone may increase the hypotensive activities of Amifostine.
BrimonidineBrimonidine may increase the antihypertensive activities of Metolazone.
BuprenorphineThe risk or severity of adverse effects can be increased when Buprenorphine is combined with Metolazone.
ButabarbitalButabarbital may increase the orthostatic hypotensive activities of Metolazone.
ButethalButethal may increase the orthostatic hypotensive activities of Metolazone.
ButorphanolThe risk or severity of adverse effects can be increased when Butorphanol is combined with Metolazone.
CaffeineThe risk or severity of adverse effects can be increased when Caffeine is combined with Metolazone.
CanagliflozinThe therapeutic efficacy of Canagliflozin can be decreased when used in combination with Metolazone.
CarbamazepineThe risk or severity of adverse effects can be increased when Metolazone is combined with Carbamazepine.
ChlorphenamineThe risk or severity of adverse effects can be increased when Chlorphenamine is combined with Metolazone.
ChlorpropamideThe therapeutic efficacy of Chlorpropamide can be decreased when used in combination with Metolazone.
CodeineThe risk or severity of adverse effects can be increased when Codeine is combined with Metolazone.
ColesevelamColesevelam can cause a decrease in the absorption of Metolazone resulting in a reduced serum concentration and potentially a decrease in efficacy.
CyclophosphamideThe risk or severity of adverse effects can be increased when Metolazone is combined with Cyclophosphamide.
DexketoprofenThe risk or severity of adverse effects can be increased when Dexketoprofen is combined with Metolazone.
DiazoxideThe risk or severity of adverse effects can be increased when Metolazone is combined with Diazoxide.
DigoxinThe risk or severity of adverse effects can be increased when Metolazone is combined with Digoxin.
DihydrocodeineThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Metolazone.
DihydrotachysterolMetolazone may increase the hypercalcemic activities of Dihydrotachysterol.
DofetilideMetolazone may increase the QTc-prolonging activities of Dofetilide.
DuloxetineMetolazone may increase the orthostatic hypotensive activities of Duloxetine.
EthanolEthanol may increase the orthostatic hypotensive activities of Metolazone.
FentanylThe risk or severity of adverse effects can be increased when Fentanyl is combined with Metolazone.
FludrocortisoneFludrocortisone may increase the hypokalemic activities of Metolazone.
FlunisolideFlunisolide may increase the hypokalemic activities of Metolazone.
GliclazideThe therapeutic efficacy of Gliclazide can be decreased when used in combination with Metolazone.
GlimepirideThe therapeutic efficacy of Glimepiride can be decreased when used in combination with Metolazone.
GliquidoneThe therapeutic efficacy of Gliquidone can be decreased when used in combination with Metolazone.
GlyburideThe therapeutic efficacy of Glyburide can be decreased when used in combination with Metolazone.
HeptabarbitalHeptabarbital may increase the orthostatic hypotensive activities of Metolazone.
HexobarbitalHexobarbital may increase the orthostatic hypotensive activities of Metolazone.
HydrocodoneThe risk or severity of adverse effects can be increased when Hydrocodone is combined with Metolazone.
HydromorphoneThe risk or severity of adverse effects can be increased when Hydromorphone is combined with Metolazone.
InfliximabThe therapeutic efficacy of Metolazone can be decreased when used in combination with Infliximab.
Insulin AspartThe therapeutic efficacy of Insulin Aspart can be decreased when used in combination with Metolazone.
Insulin DetemirThe therapeutic efficacy of Insulin Detemir can be decreased when used in combination with Metolazone.
Insulin GlargineThe therapeutic efficacy of Insulin Glargine can be decreased when used in combination with Metolazone.
Insulin GlulisineThe therapeutic efficacy of Insulin Glulisine can be decreased when used in combination with Metolazone.
Insulin HumanThe therapeutic efficacy of Insulin Regular can be decreased when used in combination with Metolazone.
Insulin LisproThe therapeutic efficacy of Insulin Lispro can be decreased when used in combination with Metolazone.
IvabradineMetolazone may increase the arrhythmogenic activities of Ivabradine.
LevodopaMetolazone may increase the orthostatic hypotensive activities of Levodopa.
LevorphanolThe risk or severity of adverse effects can be increased when Levorphanol is combined with Metolazone.
LicoriceLicorice may increase the hypokalemic activities of Metolazone.
LinagliptinThe therapeutic efficacy of Linagliptin can be decreased when used in combination with Metolazone.
LithiumMetolazone may decrease the excretion rate of Lithium which could result in a lower serum level and potentially a reduction in efficacy.
MecamylamineThe risk or severity of adverse effects can be increased when Metolazone is combined with Mecamylamine.
MetforminThe therapeutic efficacy of Metformin can be decreased when used in combination with Metolazone.
MethadoneThe risk or severity of adverse effects can be increased when Methadone is combined with Metolazone.
MethohexitalMethohexital may increase the orthostatic hypotensive activities of Metolazone.
MethylphenidateMethylphenidate may decrease the antihypertensive activities of Metolazone.
MolsidomineMolsidomine may increase the hypotensive activities of Metolazone.
MorphineThe risk or severity of adverse effects can be increased when Morphine is combined with Metolazone.
MoxonidineMoxonidine may increase the hypotensive activities of Metolazone.
NalbuphineThe risk or severity of adverse effects can be increased when Nalbuphine is combined with Metolazone.
NicorandilNicorandil may increase the hypotensive activities of Metolazone.
ObinutuzumabMetolazone may increase the hypotensive activities of Obinutuzumab.
OrciprenalineOrciprenaline may increase the hypokalemic activities of Metolazone.
OxcarbazepineThe risk or severity of adverse effects can be increased when Metolazone is combined with Oxcarbazepine.
OxycodoneThe risk or severity of adverse effects can be increased when Oxycodone is combined with Metolazone.
OxymorphoneThe risk or severity of adverse effects can be increased when Oxymorphone is combined with Metolazone.
ParoxetineParoxetine may increase the activities of Metolazone.
PentazocineThe risk or severity of adverse effects can be increased when Pentazocine is combined with Metolazone.
PentobarbitalPentobarbital may increase the orthostatic hypotensive activities of Metolazone.
PentoxifyllinePentoxifylline may increase the hypotensive activities of Metolazone.
PerindoprilMetolazone may increase the hypotensive activities of Perindopril.
PethidineThe risk or severity of adverse effects can be increased when Pethidine is combined with Metolazone.
PhenelzinePhenelzine may increase the orthostatic hypotensive activities of Metolazone.
PorfimerMetolazone may increase the photosensitizing activities of Porfimer.
PrimidonePrimidone may increase the orthostatic hypotensive activities of Metolazone.
ProcyclidineThe serum concentration of Metolazone can be increased when it is combined with Procyclidine.
QuinineQuinine may increase the hypotensive activities of Metolazone.
RemifentanilThe risk or severity of adverse effects can be increased when Remifentanil is combined with Metolazone.
RepaglinideThe therapeutic efficacy of Repaglinide can be decreased when used in combination with Metolazone.
RisperidoneMetolazone may increase the hypotensive activities of Risperidone.
RituximabMetolazone may increase the hypotensive activities of Rituximab.
SaxagliptinThe therapeutic efficacy of Saxagliptin can be decreased when used in combination with Metolazone.
SecobarbitalSecobarbital may increase the orthostatic hypotensive activities of Metolazone.
SufentanilThe risk or severity of adverse effects can be increased when Sufentanil is combined with Metolazone.
SulpirideThe risk or severity of adverse effects can be increased when Metolazone is combined with Sulpiride.
TadalafilTadalafil may increase the antihypertensive activities of Metolazone.
TapentadolThe risk or severity of adverse effects can be increased when Tapentadol is combined with Metolazone.
TolbutamideThe therapeutic efficacy of Tolbutamide can be decreased when used in combination with Metolazone.
TopiramateMetolazone may increase the hypokalemic activities of Topiramate.
ToremifeneMetolazone may increase the hypercalcemic activities of Toremifene.
TramadolThe risk or severity of adverse effects can be increased when Tramadol is combined with Metolazone.
TranylcypromineTranylcypromine may increase the orthostatic hypotensive activities of Metolazone.
TreprostinilTreprostinil may increase the hypotensive activities of Metolazone.
ValsartanThe risk or severity of adverse effects can be increased when Valsartan is combined with Metolazone.
VardenafilVardenafil may increase the antihypertensive activities of Metolazone.
VerteporfinMetolazone may increase the photosensitizing activities of Verteporfin.
VildagliptinThe therapeutic efficacy of Vildagliptin can be decreased when used in combination with Metolazone.
YohimbineYohimbine may decrease the antihypertensive activities of Metolazone.
Food Interactions
  • Take with food to reduce gastric irritation.

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