Metolazone

Identification

Summary

Metolazone is a thiazide-like diuretic used to treat hypertension.

Brand Names
Mykrox, Zaroxolyn
Generic Name
Metolazone
DrugBank Accession Number
DB00524
Background

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.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 365.835
Monoisotopic: 365.06008979
Chemical Formula
C16H16ClN3O3S
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
  • Metolazone
  • Metolazonum
External IDs
  • SR 720-22
  • SR-720-22

Pharmacology

Indication

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

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofEdema••••••••••••
Management ofEdema••••••••••••
Used in combination to manageHigh blood pressure (hypertension)••••••••••••••••••
Management ofHigh blood pressure (hypertension)••••••••••••
Management ofMild hypertension••••••••••••
Contraindications & Blackbox Warnings
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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
Humans
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

Adverse Effects
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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.

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

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirMetolazone may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbaloparatideThe risk or severity of adverse effects can be increased when Metolazone is combined with Abaloparatide.
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.
Food Interactions
  • Take with food. Food reduces irritation.

Products

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Product Images
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) / Xuret / Zytanix (Zydus)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MetolazoneTablet5 mg/1OralH.j. Harkins Co., Inc.2017-12-08Not applicableUS flag
Mykrox TabletsTablet500 ug/1OralUNSPECIFIED2006-01-12Not applicableUS flag
ZaroxolynTablet2.5 mg/1OralCarilion Materials Management1973-11-27Not applicableUS flag
ZaroxolynTablet2.5 mg/1OralPhysicians Total Care, Inc.1973-11-272010-06-30US flag
ZaroxolynTablet2.5 mgOralSanofi Aventis1974-12-31Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MetolazoneTablet10 mg/1OralMarlex Pharmaceuticals, Inc.2022-12-01Not applicableUS flag
MetolazoneTablet5 mg/1Oralbryant ranch prepack2003-12-19Not applicableUS flag
MetolazoneTablet5 mg/1OralAmici Pharmaceuticals LLC.2021-05-15Not applicableUS flag
MetolazoneTablet2.5 mg/1OralNcs Health Care Of Ky, Inc Dba Vangard Labs2003-12-19Not applicableUS flag
MetolazoneTablet5 mg/1OralAmerican Health Packaging2020-05-012023-06-30US flag

Categories

ATC Codes
C03EA12 — Metolazone and potassium-sparing agentsG01AE10 — Combinations of sulfonamidesC03BA08 — Metolazone
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Amine / Amino acid or derivatives / Aminosulfonyl compound / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carboxamide group / Carboxylic acid derivative
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
sulfonamide, organochlorine compound, quinazolines (CHEBI:64354)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
TZ7V40X7VX
CAS number
17560-51-9
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

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. [Article]
Human Metabolome Database
HMDB0014665
KEGG Drug
D00431
PubChem Compound
4170
PubChem Substance
46509058
ChemSpider
4026
BindingDB
25899
RxNav
6916
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
FDA label
Download (834 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentChronic Heart Failure (CHF) / Congestive Heart Failure (CHF) / Diuretics Drug Reactions1
4CompletedTreatmentHeart Failure1
4CompletedTreatmentRapid Ventricular Response Atrial Fibrillation1
4Not Yet RecruitingTreatmentAcute Decompensated Heart Failure (ADHF) / Edema / Volume Overload1
4Not Yet RecruitingTreatmentAcute Heart Failure (AHF)1

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-MSsplash10-0f8j-3597000000-ad3d0d3d7130fb037587
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0aor-1494000000-aae5f0a5c86e9d0828e2
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0bvi-2960000000-1eed022b28a6bb140f60
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0aor-1494000000-aae5f0a5c86e9d0828e2
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0bvi-2960000000-1eed022b28a6bb140f60
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-0009000000-3592de7bba59f8eba495
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-0009000000-5c44fe8875411507a233
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-0019000000-b97f3440390125699c90
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-4019000000-b4d7a08b0eb78db8c42b
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-003u-9344000000-5be9aaf8048b73809e0e
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-05r0-9530000000-ced2c186ef813b060094
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-190.8708226
predicted
DarkChem Lite v0.1.0
[M-H]-177.16985
predicted
DeepCCS 1.0 (2019)
[M+H]+190.8781226
predicted
DarkChem Lite v0.1.0
[M+H]+179.52783
predicted
DeepCCS 1.0 (2019)
[M+Na]+191.2131226
predicted
DarkChem Lite v0.1.0
[M+Na]+185.62099
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
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. [Article]

Drug created at June 13, 2005 13:24 / Updated at May 29, 2024 19:09