U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry RACEMIC
Molecular Formula C16H16ClN3O3S
Molecular Weight 365.8362
Optical Activity ( + / - )
Defined Stereocenters 0 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of METOLAZONE

SMILES

Cc1ccccc1N2C(C)Nc3cc(c(cc3C2=O)S(=O)(=O)N)Cl

InChI

InChIKey=AQCHWTWZEMGIFD-UHFFFAOYSA-N
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)

HIDE SMILES / InChI
Metolazone is a thiazide-like diuretic marketed under the brand names Mykrox and Zaroxolyn. Zaroxolyn is indicated for the treatment of salt and water retention including: • Edema accompanying congestive heart failure; • Edema accompanying renal diseases including the nephrotic syndrome and states of diminished renal function. Zaroxolyn is also indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class. Metolazone is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. 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. 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.

Originator

Curator's Comment:: Metolazone was developed in the 1970s by an Indian-born chemist named Dr. Bola Vithal Shetty.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
ZAROXOLYN

Approved Use

Metolazone tablets USP are indicated for the treatment of salt and water retention including: • edema accompanying congestive heart failure; • edema accompanying renal diseases, including the nephrotic syndrome and states of diminished renal function. Metolazone tablets USP are also indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class. Mykrox® tablets, a more rapidly available form of metolazone, are intended for the treatment of new patients with mild to moderate hypertension. A dose titration is necessary if Mykrox® tablets are to be substituted for Zaroxolyn® tablets and other formulations of metolazone that share its slow and incomplete bioavailability, in the treatment of hypertension. Usage In Pregnancy The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no evidence that they are useful in the treatment of developed toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequence of pregnancy. Metolazone tablets USP are indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy (see PRECAUTIONS). Dependent edema in pregnancy resulting from restriction of venous return by the expanded uterus is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may be appropriate.

Launch Date

1.23206402E11
Primary
ZAROXOLYN

Approved Use

Metolazone tablets USP are indicated for the treatment of salt and water retention including: • edema accompanying congestive heart failure; • edema accompanying renal diseases, including the nephrotic syndrome and states of diminished renal function. Metolazone tablets USP are also indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class. Mykrox® tablets, a more rapidly available form of metolazone, are intended for the treatment of new patients with mild to moderate hypertension. A dose titration is necessary if Mykrox® tablets are to be substituted for Zaroxolyn® tablets and other formulations of metolazone that share its slow and incomplete bioavailability, in the treatment of hypertension. Usage In Pregnancy The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no evidence that they are useful in the treatment of developed toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequence of pregnancy. Metolazone tablets USP are indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy (see PRECAUTIONS). Dependent edema in pregnancy resulting from restriction of venous return by the expanded uterus is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may be appropriate.

Launch Date

1.23206402E11
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
8.225 ng/mL
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
METOLAZONE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
3.63 ng/mL
2.5 mg 1 times / day unknown, oral
dose: 2.5 mg
route of administration: Oral
experiment type: UNKNOWN
co-administered:
METOLAZONE unknown
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
50.51 ng × h/mL
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
METOLAZONE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
99.74 ng × h/mL
2.5 mg 1 times / day unknown, oral
dose: 2.5 mg
route of administration: Oral
experiment type: UNKNOWN
co-administered:
METOLAZONE unknown
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
7.47 h
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
METOLAZONE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
7.5%
2.5 mg 1 times / day unknown, oral
dose: 2.5 mg
route of administration: Oral
experiment type: UNKNOWN
co-administered:
METOLAZONE unknown
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
150 mg single, oral
Highest studied dose
Dose: 150 mg
Route: oral
Route: single
Dose: 150 mg
Sources: Page: p.197
unhealthy, 18, 19
n = 2
Health Status: unhealthy
Condition: Chronic renal failure
Age Group: 18, 19
Sex: M+F
Population Size: 2
Sources: Page: p.197
20 mg 1 times / day multiple, oral (max)
Recommended
Dose: 20 mg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg, 1 times / day
Sources:
unhealthy
Disc. AE: Hyponatremia, Hypokalemia...
AEs leading to
discontinuation/dose reduction:
Hyponatremia (severe)
Hypokalemia (severe)
Sources:
20 mg 1 times / day multiple, oral (max)
Recommended
Dose: 20 mg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg, 1 times / day
Sources: Page: p.3
unhealthy
Health Status: unhealthy
Condition: Edema
Sources: Page: p.3
Disc. AE: Azotemia, Hyperuricemia...
AEs leading to
discontinuation/dose reduction:
Azotemia
Hyperuricemia
Sources: Page: p.3
AEs

AEs

AESignificanceDosePopulation
Hypokalemia severe
Disc. AE
20 mg 1 times / day multiple, oral (max)
Recommended
Dose: 20 mg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg, 1 times / day
Sources:
unhealthy
Hyponatremia severe
Disc. AE
20 mg 1 times / day multiple, oral (max)
Recommended
Dose: 20 mg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg, 1 times / day
Sources:
unhealthy
Azotemia Disc. AE
20 mg 1 times / day multiple, oral (max)
Recommended
Dose: 20 mg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg, 1 times / day
Sources: Page: p.3
unhealthy
Health Status: unhealthy
Condition: Edema
Sources: Page: p.3
Hyperuricemia Disc. AE
20 mg 1 times / day multiple, oral (max)
Recommended
Dose: 20 mg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg, 1 times / day
Sources: Page: p.3
unhealthy
Health Status: unhealthy
Condition: Edema
Sources: Page: p.3
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG


OverviewOther

Other InhibitorOther SubstrateOther Inducer


Drug as perpetrator​

Drug as perpetrator​

Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Muscle cramps, collapse, and seizures in two patients taking metolazone.
1976 Jun 5
Severe electrolyte disturbances associated with metolazone and furosemide.
1978 Apr
Hypoplastic anemia associated with metolazone.
1979 Jul 13
Palpable acute necrotizing arteritis secondary to metolazone.
1982 Jul
Excessive potassium depletion with metolazone and furosemide.
1983 Jul-Aug
Use of a bioassay in healthy men to evaluate diuretic-spironolactone combinations.
1983 May
Case report: metolazone-associated hypercalcemia and acute pancreatitis.
1991 Oct
Vasculitis due to metolazone.
1991 Sep
Difficulties of introducing the National Service Framework for heart failure into general practice in the UK.
2003 Jun
Determination of a Metolazone metabolite in human urine by high-performance liquid chromatography/diode-array detection, high-performance liquid chromatography/electrospray ionization mass spectrometry and gas chromatography/mass spectrometry.
2004
Pathophysiology of functional mutations of the thiazide-sensitive Na-Cl cotransporter in Gitelman disease.
2004 Aug
FI-chemiluminometric study of thiazides by on-line photochemical reaction.
2004 Nov 19
[The place of diuretics in the treatment of chronic heart failure. Part I].
2005
Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature.
2005 Aug
Screening procedure for detection of diuretics and uricosurics and/or their metabolites in human urine using gas chromatography-mass spectrometry after extractive methylation.
2005 Aug
How much responsibility should heart failure nurses take?
2005 Mar 16
[Diuretic therapy in heart failure].
2006 Jan-Feb
Pre-dosing metolazone with loop diuretic combination regimens.
2006 Jan-Feb
Cardiomyopathy, familial dilated.
2006 Jul 13
Reported medication use in the neonatal intensive care unit: data from a large national data set.
2006 Jun
Affinity-defining domains in the Na-Cl cotransporter: a different location for Cl- and thiazide binding.
2006 Jun 23
Beneficial effects of metolazone in a rat model of preeclampsia.
2006 Sep
Determination of metolazone in human blood by liquid chromatography with electrospray ionization tandem mass spectrometry.
2007 Jan 1
The evaluation of the diuretic action of parenteral formulations of metolazone.
2007 Jan-Feb
Treatment of diuretic refractory pleural effusions with bevacizumab in four patients with primary systemic amyloidosis.
2007 May
Premenstrual syndrome.
2007 May 1
Vitamin C-induced hyperoxaluria causing reversible tubulointerstitial nephritis and chronic renal failure: a case report.
2007 Nov 27
The pK(a) Distribution of Drugs: Application to Drug Discovery.
2007 Sep 17
Diuretics: from classical carbonic anhydrase inhibitors to novel applications of the sulfonamides.
2008
The renal cortical interstitium: morphological and functional aspects.
2008 Aug
Hydroxychloroquine-induced hyperpigmentation: the staining pattern.
2008 Dec
Acute right ventricular failure in the setting of acute pulmonary embolism or chronic pulmonary hypertension: a detailed review of the pathophysiology, diagnosis, and management.
2008 Feb
Carbonic anhydrase inhibitors. Sulfonamide diuretics revisited--old leads for new applications?
2008 Jul 21
Non-healing painful ulcers in a patient with chronic kidney disease and role of sodium thiosulfate: a case report.
2008 Sep 23
Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes.
2009
How to use diuretics in heart failure.
2009 Dec
[Renal effect of treatment for heart failure].
2009 Feb 23
How 40 kilograms of fluid retention can be overlooked: two case reports.
2009 Jan 8
Effects of increased dose of diuretics on symptoms, weight, 6-minute walk distance, and echocardiographic measurements of left ventricular systolic and diastolic function in 51 patients with symptomatic heart failure caused by reduced left ventricular ejection fraction treated with beta blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
2009 Jan-Feb
Role of SLC12A10.2, a Na-Cl cotransporter-like protein, in a Cl uptake mechanism in zebrafish (Danio rerio).
2009 May
Drugs associated with more suicidal ideations are also associated with more suicide attempts.
2009 Oct 2
Characterizing environmental and phenotypic associations using information theory and electronic health records.
2009 Sep 17
Advances in systolic heart failure.
2010 Apr 27
Development of a list of potentially inappropriate drugs for the korean elderly using the delphi method.
2010 Dec
Clinical effectiveness of telmisartan alone or in combination therapy for controlling blood pressure and vascular risk in the elderly.
2010 Dec 3
Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative.
2010 Mar
A single residue in transmembrane domain 11 defines the different affinity for thiazides between the mammalian and flounder NaCl transporters.
2010 Nov
Improved outcomes with early collaborative care of ambulatory heart failure patients discharged from the emergency department.
2010 Nov 2
Screening of a chemical library reveals novel PXR-activating pharmacologic compounds.
2015 Jan 5
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.
2015 May 18
Patents

Patents

Sample Use Guides

Usual Adult Dose for Hypertension Initial dose: 2.5 mg orally once a day (Zaroxolyn) or 0.5 mg orally once a day (Mykrox). Usual Adult Dose for Edema Initial dose: 5 mg orally once a day (Zaroxolyn) or 0.5 mg orally once a day (Mykrox).
Route of Administration: Oral
In Vitro Use Guide
In flounder bladder, metolazone (100 uM) is the most potent of the thiazide diuretics, inhibiting 22Na+ uptake by Na+-Cl- cotransport by ~90%
Name Type Language
METOLAZONE
EP   HSDB   INN   JAN   MART.   MI   ORANGE BOOK   USAN   USP   USP-RS   VANDF   WHO-DD  
USAN   INN  
Official Name English
METOLAZONE [EP]
Common Name English
SR-720-22
Code English
METOLAZONE [VANDF]
Common Name English
OLDREN
Brand Name English
7-CHLORO-1,2,3,4-TETRAHYDRO-2-METHYL-4-OXO-3-O-TOLYL-6-QUINAZOLINESULFONAMIDE
Common Name English
METOZALONE
Common Name English
METOLAZONE [USP-RS]
Common Name English
METOLAZONE [EP MONOGRAPH]
Common Name English
METOLAZONE [USAN]
Common Name English
METOLAZONE [ORANGE BOOK]
Common Name English
MYKROX
Brand Name English
METOLAZONE [JAN]
Common Name English
METOLAZONE [USP MONOGRAPH]
Common Name English
ZAROXOLYN
Brand Name English
METOLAZONE [MART.]
Common Name English
METENIX
Brand Name English
NORMELAN
Brand Name English
NSC-759581
Code English
METOLAZONE [INN]
Common Name English
6-QUINAZOLINESULFONAMIDE, 7-CHLORO-1,2,3,4-TETRAHYDRO-2-METHYL-3-(2-METHYLPHENYL)-4-OXO-
Systematic Name English
METOLAZONE [WHO-DD]
Common Name English
SR 720-22
Code English
METOLAZONE [HSDB]
Common Name English
METOLAZONE [MI]
Common Name English
METAZOLINE
Common Name English
DIULO
Brand Name English
Classification Tree Code System Code
LIVERTOX 630
Created by admin on Fri Jun 25 21:01:48 UTC 2021 , Edited by admin on Fri Jun 25 21:01:48 UTC 2021
WHO-ATC C03BA08
Created by admin on Fri Jun 25 21:01:48 UTC 2021 , Edited by admin on Fri Jun 25 21:01:48 UTC 2021
WHO-VATC QC03BA08
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NDF-RT N0000175359
Created by admin on Fri Jun 25 21:01:48 UTC 2021 , Edited by admin on Fri Jun 25 21:01:48 UTC 2021
WHO-ATC C03EA12
Created by admin on Fri Jun 25 21:01:48 UTC 2021 , Edited by admin on Fri Jun 25 21:01:48 UTC 2021
NCI_THESAURUS C49185
Created by admin on Fri Jun 25 21:01:48 UTC 2021 , Edited by admin on Fri Jun 25 21:01:48 UTC 2021
WHO-VATC QC03EA12
Created by admin on Fri Jun 25 21:01:49 UTC 2021 , Edited by admin on Fri Jun 25 21:01:49 UTC 2021
NDF-RT N0000175420
Created by admin on Fri Jun 25 21:01:48 UTC 2021 , Edited by admin on Fri Jun 25 21:01:48 UTC 2021
Code System Code Type Description
WIKIPEDIA
METOLAZONE
Created by admin on Fri Jun 25 21:01:49 UTC 2021 , Edited by admin on Fri Jun 25 21:01:49 UTC 2021
PRIMARY
EVMPD
SUB08906MIG
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PRIMARY
ChEMBL
CHEMBL878
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PRIMARY
EPA CompTox
17560-51-9
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PRIMARY
FDA UNII
TZ7V40X7VX
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PRIMARY
HSDB
3367
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PRIMARY
DRUG CENTRAL
1783
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PRIMARY
LACTMED
Metolazone
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PRIMARY
INN
2627
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PRIMARY
ECHA (EC/EINECS)
241-539-3
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PRIMARY
IUPHAR
4838
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PRIMARY
CAS
17560-51-9
Created by admin on Fri Jun 25 21:01:48 UTC 2021 , Edited by admin on Fri Jun 25 21:01:48 UTC 2021
PRIMARY
NCI_THESAURUS
C650
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PRIMARY
MERCK INDEX
M7494
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PRIMARY Merck Index
USP_CATALOG
1441200
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PRIMARY USP-RS
PUBCHEM
4170
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PRIMARY
RXCUI
6916
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PRIMARY RxNorm
DRUG BANK
DB00524
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PRIMARY
MESH
D008788
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PRIMARY