metolazone Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definition	Drug id	CAS RN
	1783	17560-51-9

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: SR72022 zaroxolyn metolazone metozalone	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. Molecular weight: 365.83 Formula: C16H16ClN3O3S CLOGP: 2.06 LIPINSKI: 0 HAC: 6 HDO: 2 TPSA: 92.50 ALOGS: -3.95 ROTB: 2 Status: OFP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

SR72022
zaroxolyn
metolazone
metozalone

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.

Molecular weight: 365.83
Formula: C16H16ClN3O3S
CLOGP: 2.06
LIPINSKI: 0
HAC: 6
HDO: 2
TPSA: 92.50
ALOGS: -3.95
ROTB: 2

Status: OFP

Legend:
OFP - off patent
OFM - off market
ONP - on patent

Drug dosage:

Dose	Unit	Route
5	mg	O

ADMET properties:

Property	Value	Reference
MRTD (Maximum Recommended Therapeutic Daily Dose)	0.78 µM/kg/day	Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
BDDCS (Biopharmaceutical Drug Disposition Classification System)	3	Hosey CM, Chan R, Benet LZ
BA (Bioavailability)	65 %	Kim MT, Sedykh A, Chakravarti SK, Saiakhov RD, Zhu H
Vd (Volume of distribution)	1.60 L/kg	Lombardo F, Berellini G, Obach RS
CL (Clearance)	1.40 mL/min/kg	Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma)	0.05 %	Lombardo F, Berellini G, Obach RS
t_half (Half-life)	20 hours	Lombardo F, Berellini G, Obach RS

Approvals:

Date	Agency	Company	Orphan
Nov. 27, 1973	FDA	UCB INC

FDA Adverse Event Reporting System (Female)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Fluid retention	233.40	15.80	171	16215	50875	46618801
Cardiac failure congestive	232.18	15.80	218	16168	91532	46578144
Fluid overload	211.71	15.80	127	16259	27058	46642618
Pulmonary arterial hypertension	188.70	15.80	116	16270	25812	46643864
Right ventricular failure	187.56	15.80	98	16288	15995	46653681
Dyspnoea	125.07	15.80	430	15956	515118	46154558
Pulmonary hypertension	123.92	15.80	102	16284	35891	46633785
Drug ineffective	112.59	15.80	49	16337	677789	45991887
Oedema	104.22	15.80	123	16263	66948	46602728
Oedema peripheral	94.88	15.80	187	16199	159519	46510157
Acute kidney injury	93.69	15.80	235	16151	235620	46434056
Renal failure	69.80	15.80	135	16251	113459	46556217
Rheumatoid arthritis	57.65	15.80	8	16378	240207	46429469
Hypokalaemia	55.75	15.80	106	16280	87918	46581758
Cardiac failure	54.03	15.80	99	16287	79849	46589827
Electrolyte imbalance	53.44	15.80	46	16340	17180	46652496
Off label use	53.16	15.80	34	16352	379807	46289869
Dyspnoea exertional	52.71	15.80	76	16310	50213	46619463
Gastrointestinal haemorrhage	51.26	15.80	95	16291	77278	46592398
Cardiac failure acute	48.42	15.80	32	16354	8046	46661630
Acute respiratory failure	46.14	15.80	54	16332	29084	46640592
BRASH syndrome	45.98	15.80	10	16376	96	46669580
Hypoxia	45.32	15.80	72	16314	51766	46617910
Pulmonary oedema	44.71	15.80	71	16315	51034	46618642
Gout	42.90	15.80	34	16352	11322	46658354
Death	41.43	15.80	229	16157	335319	46334357
Atrial fibrillation	40.75	15.80	103	16283	103487	46566189
Hyperkalaemia	39.69	15.80	67	16319	50642	46619034
Ascites	39.37	15.80	56	16330	36528	46633148
Chronic kidney disease	38.84	15.80	59	16327	40812	46628864
Hospitalisation	38.48	15.80	75	16311	63310	46606366
Cor pulmonale	38.36	15.80	17	16369	1926	46667750
Transfusion	38.36	15.80	34	16352	13197	46656479
Blood potassium decreased	37.67	15.80	56	16330	38007	46631669
Urine chloride decreased	36.67	15.80	8	16378	78	46669598
Calcium deficiency	36.03	15.80	13	16373	860	46668816
Weight increased	34.24	15.80	131	16255	164342	46505334
Respiratory failure	32.92	15.80	90	16296	94726	46574950
Torsade de pointes	32.80	15.80	30	16356	12124	46657552
Urine sodium decreased	31.16	15.80	8	16378	164	46669512
Blood urea increased	30.57	15.80	41	16345	25311	46644365
Metabolic alkalosis	30.40	15.80	16	16370	2644	46667032
Hypotension	30.17	15.80	161	16225	232428	46437248
Arthralgia	28.42	15.80	53	16333	364550	46305126
Blood creatinine increased	28.00	15.80	74	16312	76329	46593347
Oxygen consumption increased	25.63	15.80	16	16370	3647	46666029
Chest pain	25.60	15.80	126	16260	176198	46493478
Infusion related reaction	25.14	15.80	3	16383	101205	46568471
Cardiorenal syndrome	24.72	15.80	9	16377	611	46669065
Neutropenia	24.17	15.80	10	16376	143194	46526482
Generalised oedema	23.31	15.80	27	16359	14372	46655304
Renal impairment	23.26	15.80	68	16318	74304	46595372
Pain in jaw	22.78	15.80	45	16341	38327	46631349
Rash	22.67	15.80	58	16328	356454	46313222
Pericardial haemorrhage	22.61	15.80	11	16375	1540	46668136
Atrial flutter	21.66	15.80	21	16365	9127	46660549
Pericardial effusion	21.66	15.80	35	16351	25508	46644168
Cholecystitis	21.56	15.80	26	16360	14440	46655236
Dermatitis exfoliative	21.34	15.80	17	16369	5699	46663977
Dehydration	21.04	15.80	111	16275	159429	46510247
Paracentesis	21.04	15.80	9	16377	936	46668740
Localised oedema	20.93	15.80	16	16370	5053	46664623
Alopecia	20.73	15.80	16	16370	162398	46507278
Joint swelling	20.39	15.80	17	16369	166056	46503620
Device leakage	20.12	15.80	16	16370	5349	46664327
Brain natriuretic peptide increased	19.91	15.80	15	16371	4635	46665041
Multiple organ dysfunction syndrome	19.88	15.80	51	16335	51659	46618017
Pulmonary arterial pressure increased	19.48	15.80	13	16373	3319	46666357
Therapeutic product effect decreased	19.21	15.80	3	16383	82598	46587078
Packed red blood cell transfusion	19.17	15.80	11	16375	2152	46667524
Vascular parkinsonism	19.10	15.80	5	16381	111	46669565
Orthopnoea	18.84	15.80	16	16370	5864	46663812
Cardiac arrest	18.78	15.80	72	16314	90327	46579349
Pulmonary arterial wedge pressure increased	18.50	15.80	6	16380	287	46669389
Dialysis	18.13	15.80	20	16366	10096	46659580
Oxygen therapy	17.96	15.80	10	16376	1847	46667829
International normalised ratio increased	17.77	15.80	46	16340	46837	46622839
Respiratory disorder	17.41	15.80	33	16353	27267	46642409
Condition aggravated	17.38	15.80	146	16240	244906	46424770
Blood potassium increased	16.83	15.80	25	16361	16942	46652734
Oxygen saturation decreased	16.83	15.80	58	16328	69106	46600570
Hypertension	16.67	15.80	27	16359	196329	46473347
Chronic obstructive pulmonary disease	16.42	15.80	51	16335	57582	46612094
Azotaemia	16.37	15.80	13	16373	4338	46665338
Cellulitis	16.29	15.80	58	16328	70230	46599446

FDA Adverse Event Reporting System (Male)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Cardiac failure congestive	276.91	16.02	253	12596	84154	29855475
Acute kidney injury	152.83	16.02	351	12498	273491	29666138
Hypokalaemia	125.73	16.02	130	12719	50062	29889567
Fluid retention	112.43	16.02	90	12759	24908	29914721
Pulmonary hypertension	90.87	16.02	71	12778	18965	29920664
Cardiac failure	85.82	16.02	139	12710	83279	29856350
Hypotension	84.01	16.02	231	12618	200334	29739295
Fluid overload	67.78	16.02	60	12789	19032	29920597
Oedema	63.49	16.02	85	12764	42908	29896721
Oedema peripheral	58.93	16.02	136	12713	105696	29833933
Chronic kidney disease	54.63	16.02	74	12775	37764	29901865
Pulmonary arterial hypertension	53.95	16.02	39	12810	9262	29930367
Dyspnoea	53.28	16.02	282	12567	333013	29606616
Blood creatinine increased	50.38	16.02	117	12732	91258	29848371
Renal failure	50.35	16.02	145	12704	128821	29810808
Right ventricular failure	45.03	16.02	33	12816	8003	29931626
Blood urea increased	38.80	16.02	57	12792	31324	29908305
Weight increased	38.10	16.02	93	12756	74820	29864809
Drug ineffective	36.67	16.02	56	12793	340331	29599298
Polyuria	36.47	16.02	28	12821	7278	29932351
Hyponatraemia	34.78	16.02	84	12765	67118	29872511
Febrile neutropenia	34.67	16.02	3	12846	106690	29832939
Dehydration	34.60	16.02	124	12725	123415	29816214
Hypovolaemia	34.49	16.02	29	12820	8576	29931053
Necrotising oesophagitis	34.31	16.02	11	12838	413	29939216
Generalised oedema	31.90	16.02	32	12817	11853	29927776
Syncope	28.87	16.02	91	12758	84812	29854817
Gastrointestinal haemorrhage	27.97	16.02	89	12760	83357	29856272
Asthenia	27.84	16.02	176	12673	221114	29718515
Blood potassium decreased	27.78	16.02	35	12814	16627	29923002
Off label use	25.85	16.02	42	12807	249248	29690381
Transfusion	25.58	16.02	23	12826	7438	29932191
Cellulitis	24.75	16.02	59	12790	46725	29892904
Blood chloride decreased	24.44	16.02	17	12832	3796	29935833
Blood sodium decreased	24.38	16.02	32	12817	15824	29923805
Orthopnoea	23.99	16.02	18	12831	4522	29935107
Brain natriuretic peptide increased	23.58	16.02	17	12832	4018	29935611
Chronic obstructive pulmonary disease	21.06	16.02	55	12794	46071	29893558
Atrial fibrillation	21.05	16.02	97	12752	108027	29831602
Pulmonary oedema	19.63	16.02	52	12797	43923	29895706
Ventricular tachycardia	19.54	16.02	36	12813	23826	29915803
Neutropenia	19.40	16.02	16	12833	128524	29811105
Condition aggravated	18.77	16.02	112	12737	137754	29801875
Pain in jaw	17.87	16.02	24	12825	12132	29927497
Product use in unapproved indication	17.42	16.02	5	12844	73688	29865941
Renal injury	17.00	16.02	23	12826	11706	29927923
International normalised ratio increased	16.97	16.02	52	12797	47687	29891942
Azotaemia	16.45	16.02	15	12834	4937	29934692
Interstitial lung disease	16.39	16.02	3	12846	60194	29879435
Acute respiratory failure	16.34	16.02	35	12814	25815	29913814

Pharmacologic Action:

Source	Code	Description
ATC	C03BA08	CARDIOVASCULAR SYSTEM DIURETICS LOW-CEILING DIURETICS, EXCL. THIAZIDES Sulfonamides, plain
ATC	C03EA12	CARDIOVASCULAR SYSTEM DIURETICS DIURETICS AND POTASSIUM-SPARING AGENTS IN COMBINATION Low-ceiling diuretics and potassium-sparing agents
FDA PE	N0000175359	Increased Diuresis
FDA EPC	N0000175420	Thiazide-like Diuretic
MeSH PA	D000959	Antihypertensive Agents
MeSH PA	D002317	Cardiovascular Agents
MeSH PA	D004232	Diuretics
MeSH PA	D049990	Membrane Transport Modulators
MeSH PA	D045283	Natriuretic Agents
MeSH PA	D049993	Sodium Chloride Symporter Inhibitors
CHEBI has role	CHEBI:35498	diuretics
CHEBI has role	CHEBI:35674	antihypertensive
CHEBI has role	CHEBI:50184	ion-transport inhibitors

Drug Use (View source of the data)

Disease	Relation	SNOMED_ID	DOID
Hypertensive disorder	indication	38341003	DOID:10763
Renal Disease with Edema	indication
Peripheral Edema due to Chronic Heart Failure	indication
Pulmonary Edema due to Chronic Heart Failure	indication
Anuria	contraindication	2472002	DOID:2983
Hypercholesterolemia	contraindication	13644009
Hepatic encephalopathy	contraindication	13920009	DOID:13413
Orthostatic hypotension	contraindication	28651003
Hypokalemia	contraindication	43339004
Pregnancy-induced hypertension	contraindication	48194001
Systemic lupus erythematosus	contraindication	55464009	DOID:9074
Sympathectomy	contraindication	57071006
Acute nephropathy	contraindication	58574008
Hepatic failure	contraindication	59927004
Hypercalcemia	contraindication	66931009	DOID:12678
Hepatic coma	contraindication	72836002	DOID:12550
Diabetes mellitus	contraindication	73211009	DOID:9351
Oliguria	contraindication	83128009
Hyponatremia	contraindication	89627008
Gout	contraindication	90560007	DOID:13189
Hypomagnesemia	contraindication	190855004
Persistent vomiting	contraindication	196746003
Acute pancreatitis	contraindication	197456007	DOID:2913
Severe diarrhea	contraindication	409587002
Azotemia	contraindication	445009001

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	9.66	acidic
pKa2	1.3	Basic

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
Solute carrier family 12 member 3	Transporter	P55017	S12A3_HUMAN	INHIBITOR			CHEMBL	CHEMBL
Solute carrier family 12 member 1	Transporter	Q13621	S12A1_HUMAN		Kd	8.45	WOMBAT-PK
Carbonic anhydrase 7	Enzyme	P43166	CAH7_HUMAN		Ki	8.68	CHEMBL

External reference:

ID	Source
D00431	KEGG_DRUG
4018161	VANDF
C0025854	UMLSCUI
CHEBI:64354	CHEBI
CHEMBL878	ChEMBL_ID
D008788	MESH_DESCRIPTOR_UI
DB00524	DRUGBANK_ID
4838	IUPHAR_LIGAND_ID
2627	INN_ID
TZ7V40X7VX	UNII
4170	PUBCHEM_CID
203794	RXNORM
1440	MMSL
47402	MMSL
5101	MMSL
d00299	MMSL
002310	NDDF
22198003	SNOMEDCT_US
387123003	SNOMEDCT_US

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	0185-0055	TABLET	5 mg	ORAL	ANDA	23 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	0185-5050	TABLET	2.50 mg	ORAL	ANDA	23 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	0185-5600	TABLET	10 mg	ORAL	ANDA	23 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	0378-6172	TABLET	2.50 mg	ORAL	ANDA	24 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	0378-6173	TABLET	5 mg	ORAL	ANDA	24 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	0378-6174	TABLET	10 mg	ORAL	ANDA	24 sections
metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	0527-2215	TABLET	2.50 mg	ORAL	NDA AUTHORIZED GENERIC	24 sections
metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	0527-2216	TABLET	5 mg	ORAL	NDA AUTHORIZED GENERIC	24 sections
metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	0527-2217	TABLET	10 mg	ORAL	NDA AUTHORIZED GENERIC	24 sections
metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	0904-6915	TABLET	5 mg	ORAL	NDA authorized generic	24 sections
metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	0904-6916	TABLET	2.50 mg	ORAL	NDA authorized generic	24 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	43353-890	TABLET	2.50 mg	ORAL	ANDA	24 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	43353-931	TABLET	5 mg	ORAL	ANDA	24 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	43353-999	TABLET	2.50 mg	ORAL	NDA AUTHORIZED GENERIC	24 sections
METOLAZONE	Human Prescription Drug Label	1	46708-532	TABLET	2.50 mg	ORAL	ANDA	22 sections
METOLAZONE	Human Prescription Drug Label	1	46708-533	TABLET	5 mg	ORAL	ANDA	22 sections
METOLAZONE	Human Prescription Drug Label	1	46708-534	TABLET	10 mg	ORAL	ANDA	22 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	51079-023	TABLET	2.50 mg	ORAL	ANDA	24 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	51079-024	TABLET	5 mg	ORAL	ANDA	24 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	54868-5056	TABLET	5 mg	ORAL	ANDA	23 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	54868-5104	TABLET	2.50 mg	ORAL	ANDA	23 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	54868-5119	TABLET	10 mg	ORAL	ANDA	23 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	60687-536	TABLET	2.50 mg	ORAL	NDA authorized generic	25 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	60687-547	TABLET	5 mg	ORAL	NDA authorized generic	25 sections
METOLAZONE	Human Prescription Drug Label	1	62332-532	TABLET	2.50 mg	ORAL	ANDA	22 sections
METOLAZONE	Human Prescription Drug Label	1	62332-533	TABLET	5 mg	ORAL	ANDA	22 sections
METOLAZONE	Human Prescription Drug Label	1	62332-534	TABLET	10 mg	ORAL	ANDA	22 sections
Metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	63629-7875	TABLET	5 mg	ORAL	ANDA	23 sections
metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	65580-643	TABLET	2.50 mg	ORAL	NDA AUTHORIZED GENERIC	24 sections
metolazone	HUMAN PRESCRIPTION DRUG LABEL	1	65580-644	TABLET	5 mg	ORAL	NDA AUTHORIZED GENERIC	24 sections