Absorption, Distribution and Excretion
Hydroflumethiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract
THIAZIDES ARE ABSORBED FROM GI TRACT & OWE THEIR USEFULNESS LARGELY TO THEIR EFFECTIVENESS BY ORAL ROUTE. ABSORPTION IS RELATIVELY RAPID. MOST AGENTS SHOW DEMONSTRABLE DIURETIC EFFECT WITHIN HR AFTER ORAL ADMIN. /THIAZIDE DIURETICS/
IN GENERAL, THIAZIDES WITH RELATIVELY LONG DURATIONS OF ACTION SHOW PROPORTIONATELY HIGH DEGREE OF BINDING TO PLASMA PROTEINS & ARE REABSORBED BY RENAL TUBULES. ... DRUG PASSES READILY THROUGH PLACENTAL BARRIER TO FETUS. ALL THIAZIDES PROBABLY UNDERGO ACTIVE SECRETION IN PROXIMAL TUBULE. /THIAZIDE DIURETICS/
AFTER IV INFUSION OF HYDROFLUMETHIAZIDE, 2 DISTRIBUTION PHASES, T/2 OF 0.26 & 0.85 HR. AFTER SINGLE ORAL DOSE OF 2 UMOL/KG, T/2 BETA SHORTER THAN AFTER DOSE OF 6 UMOL/KG, WITH MEAN T/2 BETA OF 8.7 & 17.9 HR.
AFTER ORAL ADMIN OF HYDROFLUMETHIAZIDE EVERY 24 HR FOR 7 DAYS, MEAN BIOL T/2 OF 6.85 HR; MEAN T/2 OF METABOLITE WAS 17.7 HR. 0.652 OF DOSE EXCRETED UNCHANGED IN URINE, 0.049 AS METABOLITE. MEAN RENAL PLASMA CLEARANCE OF DRUG WAS 0.356 L/HR/KG.
For more Absorption, Distribution and Excretion (Complete) data for HYDROFLUMETHIAZIDE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Essentially unchanged
AFTER REPEATED ORAL ADMIN OF 100 MG EVERY 24 HR FOR 7 DAYS TO HEALTHY MALES, METABOLITE 2,4-DISULFAMYL-5-TRIFLUOROMETHYLANILINE DETERMINED.

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Biological Half-Life
It appears to have a biphasic biological half-life with an estimated alpha-phase of about 2 hours and an estimated beta-phase of about 17 hours
Half-life is 12-27 hr. /From table/
/Hydroflumethiazide has a/ estimated distribution half-life of approximately 2 hours and an estimated terminal elimination half-life of approximately 17 hours ... .

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the amount of hydroflumethiazide in breastmilk. Intense diuresis with large doses may decrease breastmilk production. Other diuretics in low doses are preferred over hydroflumethiazide.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information on hydroflumethiazide was not found as of the revision date. Intense diuresis with thiazides and thiazide-like diuretics, fluid restriction and breast binding have been used to suppress postpartum lactation. The added contribution of the diuretic to these measures, which are effective in suppressing lactation, has not been studied. There are no data on the effects of diuretics on established, ongoing lactation.

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Protein Binding
74%

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Interactions
...DISRUPTION OF URICOSURIC THERAPY BY ADMIN OF DIURETIC WHICH INCR PLASMA URIC ACID LEVELS (THIAZIDES)... /THIAZIDE DIURETICS/
CONCURRENT ADMIN OF THIAZIDE DIURETICS & MONOAMINE OXIDASE INHIBITORS MAY INCR HYPOTENSION. /THIAZIDE DIURETICS/
ELECTROLYTE DISTURBANCES PRODUCED BY /HYDROFLUMETHIAZIDE/ PREDISPOSE PATIENT TO...TOXICITY /OF DIGITALIS GLYCOSIDES/. SEVERE POTASSIUM DEPLETION MAY OCCUR /WITH CONCOMITANT CORTICOSTEROIDS, CORTICOTROPIN & AMPHOTERICIN B/. MAY ANTAGONIZE EFFECTS OF ORAL ANTICOAGULANTS.
/HYDROFLUMETHIAZIDE MAY PROLONG/ NEUROMUSCULAR BLOCKADE /OF/ NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS...TUBOCURARINE CHLORIDE OR GALLAMINE TRIETHIODIDE...RENAL CLEARANCE OF LITHIUM...DECREASED...SERUM LITHIUM /MAY INCREASE IN PATIENTS RECEIVING LITHIUM CARBONATE & LONG-TERM DIURETIC/.
For more Interactions (Complete) data for HYDROFLUMETHIAZIDE (22 total), please visit the HSDB record page.

[1].Selvaag E, et al. Phototoxicity to sulphonamide derived oral antidiabetics and diuretics. Comparative in vitro and in vivo investigations. In Vivo. 1997 Jan-Feb;11(1):103-7.

[2].Br\u00f8rs O, et al. Pharmacokinetics of a single oral dose of hydroflumethiazide in health and in cardiac failure.-. Eur J Clin Pharmacol. 1978 Nov 9;14(1):29-37.

[3].Hermansen K, et al. Effects of a thiazide diuretic (hydroflumethiazide) and a loop diuretic (bumetanide) on the endocrine pancreas: studies in vitro. Metabolism. 1985 Aug;34(8):784-9.

Hydroflumethiazide is a benzothiadiazine consisting of a 3,4-dihydro-HH-1,2,4-benzothiadiazine bicyclic system dioxygenated on sulfur and carrying trifluoromethyl and aminosulfonyl groups at positions 6 and 7 respectively. A diuretic with actions and uses similar to those of hydrochlorothiazide. It has a role as a diuretic and an antihypertensive agent. It is a benzothiadiazine and a thiazide.
A thiazide diuretic with actions and uses similar to those of hydrochlorothiazide. (From Martindale, The Extra Pharmacopoeia, 30th ed, p822)
Hydroflumethiazide is a Thiazide Diuretic. The physiologic effect of hydroflumethiazide is by means of Increased Diuresis.
Hydroflumethiazide is an intermediate-acting benzothiadiazine sulfonamide derivative belonging to the class of the thiazide diuretics.
A thiazide diuretic with actions and uses similar to those of HYDROCHLOROTHIAZIDE. (From Martindale, The Extra Pharmacopoeia, 30th ed, p822)
See also: Hydroflumethiazide; reserpine (component of).

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Drug 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.

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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.
...BENZOTHIADIAZIDES HAVE DIRECT EFFECT ON RENAL TUBULAR TRANSPORT OF SODIUM & CHLORIDE...INDEPENDENT OF ANY EFFECT ON CARBONIC ANHYDRASE. /THIAZIDE DIURETICS/
NATURE OF CHEM INTERACTION BETWEEN THIAZIDES & SPECIFIC RENAL RECEPTORS RESPONSIBLE FOR CHLORURETIC EFFECT IS NOT KNOWN; NO CRITICAL ENZYMATIC REACTIONS HAVE BEEN IDENTIFIED. /THIAZIDES/
THIAZIDES INHIBIT REABSORPTION OF SODIUM &...CHLORIDE IN DISTAL SEGMENT. ... AS CLASS...HAVE IMPORTANT ACTION ON EXCRETION OF POTASSIUM THAT RESULTS FROM INCR SECRETION OF CATION BY DISTAL TUBULE. ... GLOMERULAR FILTRATION RATE MAY BE REDUCED BY THIAZIDES, PARTICULARLY WITH IV ADMIN FOR EXPTL PURPOSES. /THIAZIDES/
THIAZIDES MAY DECR EXCRETION OF URIC ACID IN MAN, THUS INCR ITS CONCN IN PLASMA. HYPERURICEMIC EFFECT RESULTS PRIMARILY FROM INHIBITION OF TUBULAR SECRETION OF URATE. ... UNLIKE MOST OTHER NATRIURETIC AGENTS...DECR RENAL EXCRETION OF CALCIUM RELATIVE TO THAT OF SODIUM... /ENHANCE/ EXCRETION OF MAGNESIUM... /THIAZIDES/
For more Mechanism of Action (Complete) data for HYDROFLUMETHIAZIDE (11 total), please visit the HSDB record page.

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Therapeutic Uses
Antihypertensive Agents; Diuretics, Thiazide
POTENT ORALLY ADMIN DIURETIC USEFUL IN MGMNT OF EDEMA ASSOC WITH CARDIAC FAILURE, HEPATIC CIRRHOSIS, PREMENSTRUAL TENSION, & STEROID ADMIN. ...ALSO RECOMMENDED FOR TREATMENT OF MILD TO MODERATE HYPERTENSION EITHER ALONE OR IN COMBINATION WITH OTHER ANTIHYPERTENSIVE AGENTS.
EXCEPT FOR FACT THAT SMALLER DOSAGE IS REQUIRED FOR HYDROFLUMETHIAZIDE...NO CONVINCING EVIDENCE OF SIGNIFICANT DIFFERENCES IN THERAPEUTIC, METABOLIC, OR TOXIC OR SENSITIZATION IN EDEMATOUS OR HYPERTENSIVE PT OVER THAT OF PARENT COMPD, FLUMETHIAZIDE, OR PROTOTYPE CHLOROTHIAZIDE.
REFRACTORY CASES MAY REQUIRE AS MUCH AS 200 MG/DAY IN DIVIDED DOSES. DOSAGE SHOULD BE ADJUSTED TO PROVIDE MIN EFFECTIVE DOSE FOR INDIVIDUAL PT.
For more Therapeutic Uses (Complete) data for HYDROFLUMETHIAZIDE (11 total), please visit the HSDB record page.

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Drug Warnings
PERIODIC SERUM ELECTROLYTE DETERMINATION SHOULD BE DONE ON ALL PATIENTS IN ORDER TO DETECT ELECTROLYTE IMBALANCE SUCH AS HYPONATREMIA, HYPOCHLOREMIC ALKALOSIS, & HYPOKALEMIA. /THIAZIDE DIURETICS/
THIAZIDE DIURETICS ARE CONTRAINDICATED IN ANURIA, PATIENTS HYPERSENSITIVE TO THESE & OTHER SULFONAMIDE DRUGS, & IN OTHERWISE HEALTHY PREGNANT WOMEN WITH OR WITHOUT MILD EDEMA. ...SHOULD BE USED WITH CAUTION IN PATIENTS WITH RENAL DISEASE, SINCE THEY MAY PPT AZOTEMIA. /THIAZIDE DIURETICS/
One of the most common adverse effects of the thiazides is potassium depletion which occurs in most patients. Potassium depletion may cause cardiac arrhythmias and is particularly important in patients receiving cardiac glycosides because hypokalemia potentiates the cardiac toxicity (e.g., increased ventricular irritability) of these agents. Potassium concentrations may be especially low in patients with primary or secondary aldosteronism, in patients with a low potassium intake, in those receiving other potassium-depleting drugs, and in patients with other losses of potassium, as in vomiting and diarrhea. Intermittent rather than continuous administration of the thiazides and/or ingestion of potassium-rich foods may reduce or prevent potassium depletion; however, prophylactic administration of a potassium supplement such as potassium chloride solution or a potassium-sparing diuretic may be necessary in patients whose serum potassium concentration is less than about 3 mEq/L. Enteric-coated potassium-containing tablets should not be used because of the possibility of GI ulceration. /Thiazides/
Hypercalcemia may also occur infrequently in patients receiving thiazides, especially in patients receiving vitamin D or having mild hyperparathyroidism. Hypomagnesemia may also occur. /Thiazides/
For more Drug Warnings (Complete) data for HYDROFLUMETHIAZIDE (24 total), please visit the HSDB record page.

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Pharmacodynamics
Hydroflumethiazide is an oral thiazide used to treat hypertension and edema. High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. Like other thiazides, Hydroflumethiazide promotes water loss from the body (diuretics). Thiazides inhibit Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue.

C8H8F3N3O4S2

331.29

330.991

135-09-1

Hydroflumethiazide-13C,d2;1189877-11-9;Hydroflumethiazide-15N2,13C,d2

3647

CRYSTALS
White to cream colored, finely divided, crystalline powder

1.678g/cm3

531.6ºC at 760 mmHg

272-273ºC

275.3ºC

2.2E-11mmHg at 25°C

1.55

3.342

3

10

1

20

578

0

C1=C(C(=CC2=C1NCNS2(=O)=O)S(=O)(=O)N)C(F)(F)F

DMDGGSIALPNSEE-UHFFFAOYSA-N

InChI=1S/C8H8F3N3O4S2/c9-8(10,11)4-1-5-7(2-6(4)19(12,15)16)20(17,18)14-3-13-5/h1-2,13-14H,3H2,(H2,12,15,16)

1,1-dioxo-6-(trifluoromethyl)-3,4-dihydro-2H-1λ6,2,4-benzothiadiazine-7-sulfonamide

Glomerulin Diuredemina Hydroflumethiazide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~377.32 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)