Identification

Name
Metolazone
Accession Number
DB00524  (APRD01109)
Type
Small Molecule
Groups
Approved
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
External IDs
SR 720-22
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MetolazoneTablet5 mg/1OralH.j. Harkins Co., Inc.2017-12-08Not applicableUs
ZaroxolynTablet5 mg/1OralPhysicians Total Care, Inc.1973-11-272012-06-30Us
ZaroxolynTablet2.5 mgOralSanofi Aventis1974-12-31Not applicableCanada
ZaroxolynTablet5 mg/1OralUnither Pharmaceuticals1973-11-272015-11-30Us
ZaroxolynTablet2.5 mg/1OralCarilion Materials Management1973-11-27Not applicableUs
ZaroxolynTablet2.5 mg/1OralPhysicians Total Care, Inc.1973-11-272010-06-30Us
ZaroxolynTablet5 mgOralAventis Pharma Ltd.1974-12-312003-07-22Canada
ZaroxolynTablet2.5 mg/1OralUnither Pharmaceuticals1973-11-272015-04-30Us
Zaroxolyn Tab 10mgTablet10 mgOralRhone Poulenc Rorer1974-12-311998-08-12Canada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MetolazoneTablet2.5 mg/1OralNcs Health Care Of Ky, Inc Dba Vangard Labs2010-01-18Not applicableUs
MetolazoneTablet2.5 mg/1OralLannett Company, Inc.1973-11-27Not applicableUs
MetolazoneTablet2.5 mg/1OralAphena Pharma Solutions Tennessee, Inc.2004-01-06Not applicableUs
MetolazoneTablet2.5 mg/1OralPhysicians Total Care, Inc.2004-07-06Not applicableUs
MetolazoneTablet2.5 mg/1OralEon Labs, Inc.2003-12-19Not applicableUs
MetolazoneTablet5 mg/1OralAmerincan Health Packaging2010-10-042014-05-31Us
MetolazoneTablet10 mg/1OralUpstate Pharma, LLC1973-11-27Not applicableUs
MetolazoneTablet2.5 mg/1OralCardinal Health2011-01-142016-10-31Us
MetolazoneTablet10 mg/1OralCarilion Materials Management2004-10-19Not applicableUs
MetolazoneTablet5 mg/1OralMylan Institutional2005-02-01Not applicableUs
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Mykrox TabletsMetolazone (500 ug/1)TabletOralUNSPECIFIED2006-01-12Not applicableUs
International/Other Brands
Diulo / Diurem (Cipla) / Metadure (Micro Labs) / Metenix (IFET) / Metolaz (Navana) / Metoral (Dr. Reddy's) / Metoz (Centaur) / Metozone (Ying Yuan) / Mykrox (Celltech) / Pavedal (Pharma Investi) / Zaroxolyn / Zytanix (Zydus)
Categories
UNII
TZ7V40X7VX
CAS number
17560-51-9
Weight
Average: 365.835
Monoisotopic: 365.06008979
Chemical Formula
C16H16ClN3O3S
InChI Key
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

Pharmacology

Indication

For the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class.

Associated Conditions
Pharmacodynamics

Metolazone 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 action

The 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.

TargetActionsOrganism
ASolute carrier family 12 member 3
inhibitor
Human
Absorption

Peak blood levels are obtained within 2 to 4 hours of oral administration. The rate and extent of absorption are formulation dependent.

Volume of distribution
Not Available
Protein binding

50-70% 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 elimination

Most of the drug is excreted in the unconverted form in the urine.

Half life

Approximately 14 hours.

Clearance
Not Available
Toxicity

Symptoms 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
PathwayCategory
Metolazone Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(2-benzhydryloxyethyl)diethyl-methylammonium iodideThe serum concentration of Metolazone can be increased when it is combined with (2-benzhydryloxyethyl)diethyl-methylammonium iodide.
1alpha-Hydroxyvitamin D5The risk or severity of hypercalcemia can be increased when Metolazone is combined with 1alpha-Hydroxyvitamin D5.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Metolazone.
AbacavirMetolazone may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbediterolAbediterol may increase the hypokalemic activities of Metolazone.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Metolazone.
AcebutololMetolazone may increase the hypotensive activities of Acebutolol.
AceclofenacThe therapeutic efficacy of Metolazone can be decreased when used in combination with Aceclofenac.
AcetaminophenAcetaminophen may decrease the excretion rate of Metolazone which could result in a higher serum level.
AcetarsolMetolazone may decrease the excretion rate of Acetarsol which could result in a higher serum level.
Food Interactions
  • Take with food to reduce gastric irritation.

References

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
Human Metabolome Database
HMDB0014665
KEGG Drug
D00431
PubChem Compound
4170
PubChem Substance
46509058
ChemSpider
4026
BindingDB
25899
ChEBI
64354
ChEMBL
CHEMBL878
Therapeutic Targets Database
DAP000749
PharmGKB
PA164781022
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Metolazone
ATC Codes
C03BA08 — MetolazoneC03EA12 — Metolazone and potassium-sparing agentsG01AE10 — Combinations of sulfonamides
AHFS Codes
  • 40:28.24 — Thiazide-like Diuretics
FDA label
Download (834 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers3
1RecruitingTreatmentCongestive Heart Failure (CHF) / Prophylaxis of cardiomyopathy1
4CompletedTreatmentRapid Ventricular Response Atrial Fibrillation1
4Enrolling by InvitationTreatmentAcute Heart Failure (AHF) / Cardiovascular Disease (CVD) / Heart Failure With Reduced Ejection Fraction (HFrEF) / Heart Failure, Unspecified1
4Enrolling by InvitationTreatmentHeart Failure, Unspecified1
4TerminatedTreatmentAcute Decompensated Heart Failure (ADHF)1
Not AvailableUnknown StatusTreatmentHypernatremia / Respiratory Failure / Volume Overload1
Not AvailableWithdrawnTreatmentCongestive Heart Failure (CHF)2

Pharmacoeconomics

Manufacturers
  • Gd searle llc
  • Mylan pharmaceuticals inc
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • Ucb inc
Packagers
  • Amerisource Health Services Corp.
  • Cardinal Health
  • Caremark LLC
  • Diversified Healthcare Services Inc.
  • Eon Labs
  • Mckesson Corp.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Pharmaceutical Utilization Management Program VA Inc.
  • Physicians Total Care Inc.
  • Prepackage Specialists
  • Resource Optimization and Innovation LLC
  • Sandhills Packaging Inc.
  • Southwood Pharmaceuticals
  • Teva Pharmaceutical Industries Ltd.
  • UCB Pharma
  • UDL Laboratories
  • Upstate Pharma LLC
  • Vangard Labs Inc.
Dosage forms
FormRouteStrength
TabletOral10 mg/1
TabletOral2.5 mg/1
TabletOral5 mg/1
TabletOral500 ug/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.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)256 °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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0aor-1494000000-aae5f0a5c86e9d0828e2
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0bvi-2960000000-1eed022b28a6bb140f60

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Quinazolines
Alternative Parents
Toluenes / Secondary alkylarylamines / Organosulfonamides / Aryl chlorides / Vinylogous amides / Tertiary carboxylic acid amides / Aminosulfonyl compounds / Lactams / Amino acids and derivatives / Azacyclic compounds
show 5 more
Substituents
Quinazoline / Secondary aliphatic/aromatic amine / Toluene / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Organosulfonic acid amide / Organic sulfonic acid or derivatives / Vinylogous amide
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
sulfonamide, organochlorine compound, quinazolines (CHEBI:64354)

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]

Drug created on June 13, 2005 07:24 / Updated on September 25, 2018 17:45