DT-Web

DB00774 - Hydroflumethiazide


Identification
Name Hydroflumethiazide
Accession Number DB00774 (APRD01020)
Type small molecule
Description A thiazide diuretic with actions and uses similar to those of hydrochlorothiazide. (From Martindale, The Extra Pharmacopoeia, 30th ed, p822)
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 331.292
Groups approved
Monoisotopic Weight 330.990831754
Pharmacology
Indication Used as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Also used in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the more severe forms of hypertension.
Mechanism of action Hydroflumethiazide is a thiazide diuretic that inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, Hydroflumethiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.
Absorption Hydroflumethiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract
Protein binding 74%
Biotransformation Essentially unchanged
Route of elimination Not Available
Toxicity Overdoses lead to diuresis, lethargy progressing to coma, with minimal cardiorespiratory depression and with or without significant serum electrolyte changes or dehydration.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Digoxin Possible electrolyte variations and arrhythmias
Lithium The thiazide diuretic, hydroflumethiazide, may increase serum levels of lithium.
Trandolapril The thiazide diuretic, Hydroflumethiazide, may increase the hypotensive effect of Trandolapril. Hydroflumethiazide may also increase the nephrotoxicity of Trandolapril. Monitor for postural hypotension at initiation of concomitant therapy and renal dysfunction during chronic therapy.
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food Interactions Not Available

Targets


Solute carrier family 12 member 1
Name Solute carrier family 12 member 1
Gene Name SLC12A1
Pharmacological action yes
Actions inhibitor
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. - Pubmed
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
DTHybrid score 0.7004
Carbonic anhydrase 1
Name Carbonic anhydrase 1
Gene Name CA1
Pharmacological action unknown
Actions inhibitor
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. - Pubmed
  • Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. Epub 2008 Dec 24. - Pubmed
DTHybrid score 0.9479
Carbonic anhydrase 2
Name Carbonic anhydrase 2
Gene Name CA2
Pharmacological action unknown
Actions inhibitor
References
  • Schaeffer P, Vigne P, Frelin C, Lazdunski M: Identification and pharmacological properties of binding sites for the atypical thiazide diuretic, indapamide. Eur J Pharmacol. 1990 Jul 17;182(3):503-8. - Pubmed
  • Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. Epub 2008 Dec 24. - Pubmed
DTHybrid score 1.9464
Carbonic anhydrase 4
Name Carbonic anhydrase 4
Gene Name CA4
Pharmacological action unknown
Actions inhibitor
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. - Pubmed
  • Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. Epub 2008 Dec 24. - Pubmed
DTHybrid score 0.724
Carbonic anhydrase 9
Name Carbonic anhydrase 9
Gene Name CA9
Pharmacological action unknown
Actions inhibitor
References
  • Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. Epub 2008 Dec 24. - Pubmed
DTHybrid score 0.4425
Carbonic anhydrase 12
Name Carbonic anhydrase 12
Gene Name CA12
Pharmacological action unknown
Actions inhibitor
References
  • Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. Epub 2008 Dec 24. - Pubmed
DTHybrid score 0.4426
Sodium/potassium-transporting ATPase alpha-1 chain
Name Sodium/potassium-transporting ATPase alpha-1 chain
Gene Name ATP1A1
Pharmacological action unknown
Actions other/unknown
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. - Pubmed
DTHybrid score 0.9281
Calcium-activated potassium channel subunit alpha 1
Name Calcium-activated potassium channel subunit alpha 1
Gene Name KCNMA1
Pharmacological action unknown
Actions other/unknown
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. - Pubmed
DTHybrid score 0.4431

Predictions


Id Partner name Gene Name Score
466 Solute carrier family 12 member 3 SLC12A3 0.369
1729 Solute carrier family 22 member 6 SLC22A6 0.1718
6126 Carbonic anhydrase 7 CA7 0.156
1405 Thiopurine S-methyltransferase TPMT 0.1097
6123 Carbonic anhydrase 5A, mitochondrial CA5A 0.1056
2176 Protein S100-P S100P 0.0971
6131 Carbonic anhydrase 14 CA14 0.0834
310 Solute carrier family 12 member 2 SLC12A2 0.0808
6122 Carbonic anhydrase 3 CA3 0.0795
4512 Cytochrome P450 3A4 CYP3A4 0.0739
6124 Carbonic anhydrase 5B, mitochondrial CA5B 0.0649
170 Succinate semialdehyde dehydrogenase, mitochondrial ALDH5A1 0.0539
566 Serotransferrin TF 0.0538
4757 Cytochrome P450 2C9 CYP2C9 0.0538
253 Sodium/potassium-transporting ATPase gamma chain FXYD2 0.052
6013 Cytochrome P450 2E1 CYP2E1 0.0481
587 Serum albumin ALB 0.0446
781 ATP-sensitive inward rectifier potassium channel 11 KCNJ11 0.0416
3426 Glutamine synthetase glnA 0.041
3987 Glutamine synthetase GLUL 0.041
3932 Glutathione S-transferase A2 GSTA2 0.0371
6016 Cytochrome P450 2C19 CYP2C19 0.0365
6024 Cytochrome P450 1A1 CYP1A1 0.0362
1024 Solute carrier family 22 member 11 SLC22A11 0.0351
997 Protein kinase C beta type PRKCB 0.035
53 Solute carrier family 12 member 5 SLC12A5 0.0343
663 Solute carrier family 12 member 4 SLC12A4 0.0343
634 Squalene monooxygenase SQLE 0.0327
7196 Squalene monooxygenase ERG1 0.0327
1970 Protein kinase C alpha type PRKCA 0.032
2408 Tyrosine-protein kinase SYK SYK 0.0318
158 Sodium channel protein type 1 subunit alpha SCN1A 0.0311
6127 Carbonic anhydrase-related protein CA8 0.0282
6129 Carbonic anhydrase-related protein 11 CA11 0.0281
6128 Carbonic anhydrase-related protein 10 CA10 0.0281
6133 Sodium channel subunit beta-2 SCN2B 0.0281
6132 Sodium channel subunit beta-1 SCN1B 0.0281
6134 Sodium channel subunit beta-3 SCN3B 0.0281
6135 Sodium channel subunit beta-4 SCN4B 0.0281
6150 Solute carrier organic anion transporter family member 4C1 SLCO4C1 0.028
1025 Aquaporin-1 AQP1 0.0263
4119 Cytochrome P450 2D6 CYP2D6 0.0257
6130 Carbonic anhydrase 13 CA13 0.025
2236 Casein kinase II subunit alpha CSNK2A1 0.0247
3803 Sodium channel protein type 3 subunit alpha SCN3A 0.0246
304 Solute carrier family 12 member 7 SLC12A7 0.0243
157 Solute carrier family 12 member 6 SLC12A6 0.0242
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0241
964 Voltage-dependent T-type calcium channel subunit alpha-1H CACNA1H 0.0235
215 Sodium channel protein type 11 subunit alpha SCN11A 0.0232
6142 Solute carrier family 22 member 8 SLC22A8 0.0229
6263 cAMP-dependent protein kinase catalytic subunit alpha PRKACA 0.0217
3802 Sodium channel protein type 2 subunit alpha SCN2A 0.0217
3623 Divalent-cation tolerance protein cutA cutA 0.0206
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.02
3804 Sodium channel protein type 4 subunit alpha SCN4A 0.02
1995 Sodium channel protein type 9 subunit alpha SCN9A 0.0198
241 Calcium-transporting ATPase type 2C member 1 ATP2C1 0.0197
5718 Cytochrome P450 2A6 CYP2A6 0.0196
537 ATP synthase delta chain, mitochondrial ATP5D 0.0188
15 Voltage-dependent T-type calcium channel subunit alpha-1I CACNA1I 0.0179
559 NADH-ubiquinone oxidoreductase chain 1 MT-ND1 0.0174
482 Glycine receptor subunit alpha-1 GLRA1 0.017
535 Voltage-dependent T-type calcium channel subunit alpha-1G CACNA1G 0.017
382 Glutamate receptor, ionotropic kainate 1 GRIK1 0.0168
1588 Multidrug resistance protein 1 ABCB1 0.0159
6017 Cholesterol side-chain cleavage enzyme, mitochondrial CYP11A1 0.0156
6020 Aldehyde oxidase AOX1 0.015
6158 Solute carrier organic anion transporter family member 1C1 SLCO1C1 0.0143
705 Glutamate receptor 1 GRIA1 0.0137
3226 UPF0234 protein HI1034 HI_1034 0.0135
3384 Macrophage migration inhibitory factor MIF 0.0132
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0131
3939 Amine oxidase [flavin-containing] B MAOB 0.0131
3941 Amine oxidase [flavin-containing] A MAOA 0.013
4200 Cytochrome P450 1A2 CYP1A2 0.013
858 Potassium voltage-gated channel subfamily A member 1 KCNA1 0.0124
6157 Solute carrier organic anion transporter family member 1B3 SLCO1B3 0.0124
20 Prostaglandin G/H synthase 1 PTGS1 0.0122
4924 Cytochrome P450 2C8 CYP2C8 0.0121
462 Intermediate conductance calcium-activated potassium channel protein 4 KCNN4 0.0117
6040 6-phosphogluconate dehydrogenase, decarboxylating PGD 0.0114
3105 M-phase inducer phosphatase 2 CDC25B 0.0108
6152 Solute carrier organic anion transporter family member 2A1 SLCO2A1 0.0108
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0108
741 Potassium voltage-gated channel subfamily KQT member 1 KCNQ1 0.0103
2184 Cystic fibrosis transmembrane conductance regulator CFTR 0.0095
6047 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A PDE1A 0.0093
5692 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B PDE1B 0.0087
392 Voltage-dependent P/Q-type calcium channel subunit alpha-1A CACNA1A 0.0087
1768 Guanine nucleotide-binding protein G(I)/G(S)/G(O) gamma-2 subunit GNG2 0.0082
1571 G protein-activated inward rectifier potassium channel 1 KCNJ3 0.0082
1268 Neuropeptide S receptor NPSR1 0.0082
1581 G protein-activated inward rectifier potassium channel 2 KCNJ6 0.0082
1561 Troponin C, slow skeletal and cardiac muscles TNNC1 0.0081
4160 Voltage-dependent calcium channel subunit alpha-2/delta-2 CACNA2D2 0.008
118 Organic cation/carnitine transporter 2 SLC22A5 0.008
6935 Small conductance calcium-activated potassium channel protein 2 KCNN2 0.0077
6933 Calcium-activated potassium channel subunit beta-4 KCNMB4 0.0077
6931 Calcium-activated potassium channel subunit beta-1 KCNMB1 0.0077
6932 Calcium-activated potassium channel subunit beta-3 KCNMB3 0.0077
6934 Small conductance calcium-activated potassium channel protein 1 KCNN1 0.0077
6936 Small conductance calcium-activated potassium channel protein 3 KCNN3 0.0077
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0075
6030 Cytochrome P450 2B6 CYP2B6 0.0074
6141 Sodium/bile acid cotransporter SLC10A1 0.0071
6072 Potassium channel subfamily K member 3 KCNK3 0.0069
6073 Potassium channel subfamily K member 9 KCNK9 0.0069
3627 UPF0190 protein yedY yedY 0.0067
1392 Catenin beta-1 CTNNB1 0.0067
3352 Structural polyprotein Not Available 0.0067
3628 Structural polyprotein Not Available 0.0067
4892 Structural polyprotein Not Available 0.0067
6167 Organic solute transporter subunit beta OSTB 0.0066
6166 Organic solute transporter subunit alpha OSTA 0.0066
5463 Calcium-activated potassium channel subunit beta 2 KCNMB2 0.0063
465 Calmodulin CALM1 0.0062
6143 Solute carrier family 22 member 7 SLC22A7 0.0059
591 Glutamate [NMDA] receptor subunit 3B GRIN3B 0.0055
290 Prostaglandin G/H synthase 2 PTGS2 0.0055
6153 Solute carrier organic anion transporter family member 4A1 SLCO4A1 0.0054
514 Potassium voltage-gated channel subfamily H member 6 KCNH6 0.0052
772 Potassium voltage-gated channel subfamily H member 7 KCNH7 0.0052
837 Glutamate [NMDA] receptor subunit epsilon-1 GRIN2A 0.0051
2207 Rhodopsin RHO 0.0047
365 Dihydrofolate reductase DHFR 0.0046
2381 Dihydrofolate reductase DFR1 0.0046
2833 Dihydrofolate reductase Not Available 0.0046
2931 Dihydrofolate reductase folA 0.0046
3544 Dihydrofolate reductase folA 0.0046
3682 Dihydrofolate reductase folA 0.0046
6642 Dihydrofolate reductase folA 0.0046
6756 Dihydrofolate reductase dfrA 0.0046
260 Cytochrome P450 51 ERG11 0.0045
761 Cytochrome P450 51 ERG11 0.0045
3163 Cytochrome P450 51 cyp51 0.0045
6046 Voltage-gated calcium channel beta 1 subunit splice variant CavB1d CACNB1 0.0044
706 Glutamate [NMDA] receptor subunit 3A GRIN3A 0.0043
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.0042
805 Cytochrome P450 11B1, mitochondrial CYP11B1 0.0042
776 Bile salt export pump ABCB11 0.0041
315 Arginase-1 ARG1 0.004
6045 Voltage-dependent calcium channel subunit alpha-2/delta-3 CACNA2D3 0.004
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.0039
7 Nitric oxide synthase, inducible NOS2 0.0035
3811 Cytochrome P450 19A1 CYP19A1 0.0034
291 Nitric-oxide synthase, endothelial NOS3 0.0034
3970 Voltage-dependent N-type calcium channel subunit alpha-1B CACNA1B 0.0031
762 Voltage-dependent calcium channel subunit alpha-2/delta-1 CACNA2D1 0.0026
4110 Voltage-dependent L-type calcium channel subunit beta-2 CACNB2 0.0026
4115 Voltage-dependent L-type calcium channel subunit alpha-1D CACNA1D 0.0026
4111 Voltage-dependent L-type calcium channel subunit alpha-1S CACNA1S 0.0026
478 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C 0.0025
6107 Cytochrome P450 3A7 CYP3A7 0.0016
4118 Cytochrome P450 3A5 CYP3A5 0.0016
4037 Hypothetical protein GPX1 0.0008
4297 Hypothetical protein SP_1951 0.0008
4521 Hypothetical protein BC_2969 0.0008
4540 Hypothetical protein TM_1070 0.0008
4555 Hypothetical protein MT1739 0.0008
4569 Hypothetical protein mshD 0.0008
4578 Hypothetical protein PA3270 0.0008
4747 Hypothetical protein PA3967 0.0008
5177 Hypothetical protein TM_0096 0.0008
5194 Hypothetical protein PA1204 0.0008
5240 Hypothetical protein Rv2991 0.0008
5370 Hypothetical protein TM_1158 0.0008
5710 Hypothetical protein Tb927.5.1360 0.0008
4527 Putative hydrolase ycdX ycdX 0.0008
4536 Transcriptional regulator, IclR family TM_0065 0.0008
2501 Protein ygbM ygbM 0.0008
4545 Molybdopterin-converting factor subunit 2 moaE 0.0008
4522 Arginine N-succinyltransferase subunit alpha astA 0.0008
4106 Guanylate kinase GUK1 0.0008
4516 Guanylate kinase gmk 0.0008
4538 Hypothetical protein VC1899 VC_1899 0.0008
4529 Oxalate decarboxylase oxdC oxdC 0.0008
4514 Citrate lyase beta subunit-like protein citE 0.0008
4781 Citrate lyase beta subunit-like protein DR_1240 0.0008
4526 Oligopeptide ABC transporter, periplasmic oligopeptide-binding protein TM_1223 0.0008
4524 Mannose-6-phosphate isomerase yvyI 0.0008
4535 Glutaconyl-CoA decarboxylase subunit alpha gcdA 0.0008
4547 Iron binding protein FbpA fbpA 0.0008
4548 Gyrase B gyrB 0.0008
4546 Aminotransferase, putative TM_1131 0.0008
658 Para-aminobenzoate synthase component 1 pabB 0.0008
4515 Peripheral plasma membrane protein CASK CASK 0.0008
4496 C-terminal-binding protein 1 CTBP1 0.0008
4517 Probable butyrate kinase 2 buk2 0.0007
3261 Signal recognition particle protein ffh 0.0007
4528 Phenazine biosynthesis protein PhzD phzD1 0.0007
4533 Glyoxalase family protein BC_1747 0.0007
56 Delta-aminolevulinic acid dehydratase ALAD 0.0007
2356 Delta-aminolevulinic acid dehydratase hemB 0.0007
3613 Delta-aminolevulinic acid dehydratase hemB 0.0007
3674 Delta-aminolevulinic acid dehydratase hemB 0.0007
3759 Glutathione S-transferase gst 0.0007
4541 Glutathione S-transferase GST 0.0007
4542 Glutaminase 1 glsA1 0.0007
4544 Glutaminase 1 glsA1 0.0007
2929 (S)-2-haloacid dehalogenase dhlB 0.0007
2995 (S)-2-haloacid dehalogenase Not Available 0.0007
3237 Beta-lactamase OXA-2 bla 0.0007
4532 Gephyrin GPHN 0.0007
2230 Catalase CAT 0.0007
3249 Catalase katA 0.0007
3625 Catalase katA 0.0007
4539 Catalase katA 0.0007
4941 Catalase katB 0.0007
4531 Putative ketoacyl reductase actIII 0.0007
2775 Dihydroorotate dehydrogenase pyrD 0.0007
3467 Methylglyoxal synthase mgsA 0.0007
3583 6-phosphogluconolactonase pgl 0.0007
2525 3-phosphoshikimate 1-carboxyvinyltransferase aroA 0.0006
3201 3-phosphoshikimate 1-carboxyvinyltransferase aroA 0.0006
2688 Peptide deformylase def 0.0006
2708 Peptide deformylase def 0.0006
3004 Peptide deformylase def 0.0006
4337 Peptide deformylase def 0.0006
4338 Peptide deformylase def 0.0006
5368 Peptide deformylase def 0.0006
5371 Peptide deformylase def 0.0006
6375 Peptide deformylase def 0.0006
6378 Peptide deformylase def 0.0006
6379 Peptide deformylase def 0.0006
6776 Peptide deformylase def 0.0006
6900 Peptide deformylase def 0.0006
4534 Cytohesin-2 CYTH2 0.0006
2548 Subtilisin Carlsberg apr 0.0006
4269 Hypoxanthine-guanine phosphoribosyltransferase, putative HGPRTase 0.0006
760 Fibroblast growth factor 1 FGF1 0.0005
810 Heme oxygenase 1 HMOX1 0.0005
3391 Heme oxygenase 1 pbsA1 0.0005
3027 Streptavidin Not Available 0.0005
500 Monocarboxylate transporter 4 SLC16A3 0.0005
76 Nitric-oxide synthase, brain NOS1 0.0004
5682 Ribonuclease pancreatic RNASE1 0.0004
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