METOLAZONE, (-)-

Details

Stereochemistry	UNKNOWN
Molecular Formula	C16H16ClN3O3S
Molecular Weight	365.835
Optical Activity	( - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1NC2=CC(Cl)=C(C=C2C(=O)N1C3=C(C)C=CC=C3)S(N)(=O)=O

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

Molecular Formula	C16H16ClN3O3S
Molecular Weight	365.835
Charge	0
Count

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/017386Orig1s040.pdf | https://www.drugs.com/pro/metolazone.html

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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Thiazide-sensitive sodium-chloride cotransporter 28 Target ID: CHEMBL1876 Sources: https://www.drugbank.ca/drugs/DB00524 \| https://www.ncbi.nlm.nih.gov/pubmed/2043163 \| http://drugcentral.org/drugcard/1783/view	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hypertension 567 Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0b619826-2567-49d7-8972-b6da5e4467df&type=display	Primary		Approved 8429	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 1973
Congestive heart failure 54 Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0b619826-2567-49d7-8972-b6da5e4467df&type=display	Primary		Approved 8429	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 1973

C_max

Value	Dose	Co-administered	Analyte	Population
8.225 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29145890	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 DRUG LABEL http://products.sanofi.ca/en/zaroxolyn.pdf	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

Value	Dose	Co-administered	Analyte	Population
50.51 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29145890	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 DRUG LABEL http://products.sanofi.ca/en/zaroxolyn.pdf	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
7.47 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29145890	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
7.5% DRUG LABEL http://products.sanofi.ca/en/zaroxolyn.pdf	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

Dose	Population	Adverse events
150 mg single, oral Highest studied dose Dose: 150 mg Route: oral Route: single Dose: 150 mg Sources: https://pubmed.ncbi.nlm.nih.gov/5082545 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: https://pubmed.ncbi.nlm.nih.gov/5082545 Page: p.197	Sources: https://pubmed.ncbi.nlm.nih.gov/5082545 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: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0b619826-2567-49d7-8972-b6da5e4467df&type=display	unhealthy Health Status: unhealthy Condition: Edema Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0b619826-2567-49d7-8972-b6da5e4467df&type=display	Disc. AE: Hyponatremia, Hypokalemia... AEs leading to discontinuation/dose reduction: Hyponatremia (severe) Hypokalemia (severe) Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0b619826-2567-49d7-8972-b6da5e4467df&type=display
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: https://products.sanofi.ca/en/zaroxolyn.pdf Page: p.3	unhealthy Health Status: unhealthy Condition: Edema Sources: https://products.sanofi.ca/en/zaroxolyn.pdf Page: p.3	Disc. AE: Azotemia, Hyperuricemia... AEs leading to discontinuation/dose reduction: Azotemia Hyperuricemia Sources: https://products.sanofi.ca/en/zaroxolyn.pdf Page: p.3

AEs

AE	Significance	Dose	Population
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: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0b619826-2567-49d7-8972-b6da5e4467df&type=display	unhealthy Health Status: unhealthy Condition: Edema Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0b619826-2567-49d7-8972-b6da5e4467df&type=display
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: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0b619826-2567-49d7-8972-b6da5e4467df&type=display	unhealthy Health Status: unhealthy Condition: Edema Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0b619826-2567-49d7-8972-b6da5e4467df&type=display
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: https://products.sanofi.ca/en/zaroxolyn.pdf Page: p.3	unhealthy Health Status: unhealthy Condition: Edema Sources: https://products.sanofi.ca/en/zaroxolyn.pdf 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: https://products.sanofi.ca/en/zaroxolyn.pdf Page: p.3	unhealthy Health Status: unhealthy Condition: Edema Sources: https://products.sanofi.ca/en/zaroxolyn.pdf Page: p.3

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781			inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
UGT1A1 204		P-gp 257

Drug as perpetrator

Target	Modality	Activity
UGT1A1 254	inhibitor 3277 Sources: https://www.liebertpub.com/doi/abs/10.1089/adt.2006.050 Page: 349.0	likely
CYP3A4 1925	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252478/ Page: 8.0	yes
P-gp 1650	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252478/ Page: 8.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://onlinelibrary.wiley.com/doi/full/10.1002/clc.20945 Page: 579.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:64354	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:64354
ChemicalBook	CB4725936	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4725936
MolPort	MolPort-003-666-780	https://www.molport.com/shop/molecule-link/MolPort-003-666-780
Selleck Chemicals	Metolazone(Zaroxolyn)	http://www.selleckchem.com/products/Metolazone(Zaroxolyn).html
eMolecules	591574	https://www.emolecules.com/cgi-bin/more?vid=591574

PubMed

Title	Date	PubMed
Muscle cramps, collapse, and seizures in two patients taking metolazone.	1976 Jun 5	1276698
Severe electrolyte disturbances associated with metolazone and furosemide.	1978 Apr	635611
Hypoplastic anemia associated with metolazone.	1979 Jul 13	448877
Palpable acute necrotizing arteritis secondary to metolazone.	1982 Jul	6126318
Excessive potassium depletion with metolazone and furosemide.	1983 Jul-Aug	6883959
Use of a bioassay in healthy men to evaluate diuretic-spironolactone combinations.	1983 May	6860532
Case report: metolazone-associated hypercalcemia and acute pancreatitis.	1991 Oct	1928234
Vasculitis due to metolazone.	1991 Sep	1946137
Difficulties of introducing the National Service Framework for heart failure into general practice in the UK.	2003 Jun	12798835
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	15095363
Pathophysiology of functional mutations of the thiazide-sensitive Na-Cl cotransporter in Gitelman disease.	2004 Aug	15068971
FI-chemiluminometric study of thiazides by on-line photochemical reaction.	2004 Nov 19	15533660
[The place of diuretics in the treatment of chronic heart failure. Part I].	2005	16091650
Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature.	2005 Aug	16189620
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	16044110
How much responsibility should heart failure nurses take?	2005 Mar 16	15718175
[Diuretic therapy in heart failure].	2006 Jan-Feb	16634001
Pre-dosing metolazone with loop diuretic combination regimens.	2006 Jan-Feb	16538931
Cardiomyopathy, familial dilated.	2006 Jul 13	16839424
Reported medication use in the neonatal intensive care unit: data from a large national data set.	2006 Jun	16740839
Affinity-defining domains in the Na-Cl cotransporter: a different location for Cl- and thiazide binding.	2006 Jun 23	16624820
Beneficial effects of metolazone in a rat model of preeclampsia.	2006 Sep	16717105
Determination of metolazone in human blood by liquid chromatography with electrospray ionization tandem mass spectrometry.	2007 Jan 1	16908225
The evaluation of the diuretic action of parenteral formulations of metolazone.	2007 Jan-Feb	17303972
Treatment of diuretic refractory pleural effusions with bevacizumab in four patients with primary systemic amyloidosis.	2007 May	17326106
Premenstrual syndrome.	2007 May 1	19454075
Vitamin C-induced hyperoxaluria causing reversible tubulointerstitial nephritis and chronic renal failure: a case report.	2007 Nov 27	18042297
The pK(a) Distribution of Drugs: Application to Drug Discovery.	2007 Sep 17	19812734
Diuretics: from classical carbonic anhydrase inhibitors to novel applications of the sulfonamides.	2008	18336309
The renal cortical interstitium: morphological and functional aspects.	2008 Aug	18575881
Hydroxychloroquine-induced hyperpigmentation: the staining pattern.	2008 Dec	18727667
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	19924277
Carbonic anhydrase inhibitors. Sulfonamide diuretics revisited--old leads for new applications?	2008 Jul 21	18600270
Non-healing painful ulcers in a patient with chronic kidney disease and role of sodium thiosulfate: a case report.	2008 Sep 23	18811973
Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes.	2009	19209224
How to use diuretics in heart failure.	2009 Dec	19930980
[Renal effect of treatment for heart failure].	2009 Feb 23	19257999
How 40 kilograms of fluid retention can be overlooked: two case reports.	2009 Jan 8	19133159
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	19142162
Role of SLC12A10.2, a Na-Cl cotransporter-like protein, in a Cl uptake mechanism in zebrafish (Danio rerio).	2009 May	19279294
Drugs associated with more suicidal ideations are also associated with more suicide attempts.	2009 Oct 2	19798416
Characterizing environmental and phenotypic associations using information theory and electronic health records.	2009 Sep 17	19761567
Advances in systolic heart failure.	2010 Apr 27	20948854
Development of a list of potentially inappropriate drugs for the korean elderly using the delphi method.	2010 Dec	21818443
Clinical effectiveness of telmisartan alone or in combination therapy for controlling blood pressure and vascular risk in the elderly.	2010 Dec 3	21152242
Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative.	2010 Mar	20037146
A single residue in transmembrane domain 11 defines the different affinity for thiazides between the mammalian and flounder NaCl transporters.	2010 Nov	20719978
Improved outcomes with early collaborative care of ambulatory heart failure patients discharged from the emergency department.	2010 Nov 2	20956211
Screening of a chemical library reveals novel PXR-activating pharmacologic compounds.	2015 Jan 5	25455453
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.	2015 May 18	25811541

Patents

Sample Use Guides

In Vivo Use Guide

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%

Substance Class	Chemical Created by `admin` on `Sat Dec 16 10:21:33 GMT 2023` Edited by `admin` on `Sat Dec 16 10:21:33 GMT 2023`
Record UNII	NN9U607695
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

METOLAZONE, (-)-

Common Name

English

6-QUINAZOLINESULFONAMIDE, 7-CHLORO-1,2,3,4-TETRAHYDRO-2-METHYL-3-(2-METHYLPHENYL)-4-OXO-, (-)-

Systematic Name

English

Code System Code Type Description

FDA UNII

NN9U607695

Created by admin on Sat Dec 16 10:21:33 GMT 2023 , Edited by admin on Sat Dec 16 10:21:33 GMT 2023

PRIMARY

CAS

56436-32-9