Absorption, Distribution and Excretion
Absorption of fludrocortisone following oral administration is rapid and complete. Pharmacokinetic studies have estimated the Cmax to be 0.0012 to 0.20 μg/L with a Tmax between 0.5 and 2 hours. The AUC0-∞ of fludrocortisone after oral administration has been variably estimated to be between 1.22 to 3.07 μg.h/L.
Approximately 80% of an administered dose of fludrocortisone shows up in the urine, with the other 20% likely eliminated via fecal or biliary route.
The apparent volume of distribution of fludrocortisone is 80-85 L. Distribution into CSF appears minimal - the observed ratio of CSF drug concentration versus plasma drug concentration is 1:6.
Population pharmacokinetics have estimated the plasma clearance of fludrocortisone to be 40.8 L/h.
Elimination: Renal, mostly as inactive metabolites.
Oral: Rapidly and almost completely absorbed. Parenteral: Intramuscular: Freely soluble esters (sodium phosphate, sodium succinate) - Rapidly absorbed. Poorly soluble derivatives (acetate, acetonide, diacetate, hexacetonide, tebutate) - Slowly but completely absorbed. Local: Freely soluble esters - Less rapidly absorbed than with intramuscular injection. Poorly soluble derivatives - Slowiy but completely absorbed. /Corticosteroids (glucocorticoid effects - systemic)/

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Metabolism / Metabolites
There exists is a paucity of information regarding the specific metabolic pathway _in vivo_ of fludrocortisone. The 9α-fluorination of fludrocortisone appears to greatly simplify its metabolism as compared to other corticosteroids - while oxidation via 11-hydroxysteroid dehydrogenases has been observed, this reaction is greatly impaired as the fluorine moiety appears to confer "protection" from 11β-oxidation by these enzymes. The reduction in 11β-oxidation is thought to be one of the reasons behind fludrocortisone's profound mineralocorticoid potency. An _in vitro_ study generated only two metabolites following incubation in human liver microsomes and cytosol, namely 20β-dihydrofluorocortisol and 6β-hydroxyfluorocortisol, and did not explore in detail the potential enzymes responsible for this reaction. Given that fludrocortisone is a corticosteroid, a class of medications known to be metabolized by the CYP3A family, and is not recommended to be given with strong inhibitors/inducers of CYP3A, it is likely that the CYP3A family of enzymes contributes in some way to its metabolism (though this information does not appear to have been specifically elucidated for fludrocortisone).
STUDIED WERE KIDNEY SLICES, HOMOGENATES, & ISOLATED PERFUSED KIDNEYS. MAJOR METABOLITE: 20(EPSILON)-DIHYDRO-9ALPHA-FLUOROCORTISOL. ONLY 9ALPHA-FLUOROCORTISOL, NO METABOLITES, BOUND TO CYTOSOLIC RECEPTORS.

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Biological Half-Life
The plasma half-life of fludrocortisone has been variably reported to be between 1-3.5 hours, though prescribing information gives an approximate half-life of 18-36 hours.
> or = 3.5 hours (plasma); 18-36 hours (biological).

Protein Binding
Fludrocortisone is 70-80% protein bound in plasma, mostly to albumin and corticosteroid-binding globulin.

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Interactions
Concurrent use /of sodium-containing foods or medications/ with fludrocortisone in the treatment of Type IV renal tubular acidosis may result in hypernatremia, edema, and potentially severe increases in blood pressure;adjustment of sodium intake may be required.
In one published case report, lithium antagonized the mineralocorticoid effects of fludrocortisone; increased fludrocortisone dose and dietary sodium supplementation were required during concurrent use.
Risk of severe hypokalemia /when fludrocortisone is used concurrently with hypokalemia-causing medications/; monitoring of serum potassium concentration and cardiac function and potassium supplementation may be required.
Phenytoin and rifampin have been reported to increase 6-beta-hydroxylation of fludrocortisone, via induction of p450 liver enzymes; fludrocortisone dosage increase may be required.
For more Interactions (Complete) data for FLUDROCORTISONE (24 total), please visit the HSDB record page.

: Does fludrocortisone influence autobiographical memory retrievalA study in patients with major depression, patients with borderline personality disorder and healthy controls. Stress. 2015 Nov;18(6):718-22. doi: 10.3109/10253890.2015.1087504.

Therapeutic Uses
Anti-Inflammatory Agents, Steroidal; Mineralocorticoids, Synthetic
Fludrocortisone is used in the treatment of Type IV renal tubular acidosis associated with hyporeninemic hypoaldosteronism. Fludrocortisone is also used as an aid in diagnosing the cause of the condition. Effectiveness of fludrocortisone therapy indicated that the condition is caused by hyporeninemic hypoaldosteronism rather than by renal tubular transport dysfunction. /NOT included in US product labeling/
Fludrocortisone is used in conjunction with increased sodium intake in the treatment of idiopathic orthostatic hypotension. /NOT included in US product labeling/
Fludrocortisone is indicated in salt-losing forms of adrenogenital syndrome. /Included in US product labeling/
For more Therapeutic Uses (Complete) data for FLUDROCORTISONE (8 total), please visit the HSDB record page.

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Drug Warnings
Most adverse reactions of fludrocortisone are caused by the drug's mineralocorticoid activity (retention of sodium and water). When fludrocortisone is used in the small dosages recommended, the glucocorticoid side effects are not usually a problem, however, these effects should be kept in mind, particularly when fludrocortisone is used over a prolonged period of time or in conjunction with cortisone or a similar glucocorticoid.
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
To evaluate tolerance of fludrocortisone in older patients with hypotensive disorders... 64 patients over 65 years (mean age 80 years) with one or more hypotensive disorders (orthostatic hypotension, vasodepressor carotid sinus syncope, and/or vasodepressor neurocardiogenic syncope /were given/ fludrocortisone in daily doses of 100 ug (corrected) (72%), 50 ug (corrected) (27%), and 200 ug (corrected) (one patient). ... During follow up, 13 patients died of unrelated causes. Of the remainder 33% discontinued fludrocortisone at a mean of five months. Reasons for discontinuing treatment were hypertension, five; cardiac failure, four; depression, three; edema, three; and unspecified, two. In those who continued treatment supine systolic and diastolic blood pressure did not differ significantly from baseline (follow up two to 21 months). Hypokalemia developed in 24% at a mean of eight months; in no case was treatment withdrawn because of hypokalemia. Fludrocortisone, even in low doses, is poorly tolerated in the long term in older patients with hypotensive disorders.
The mechanism of recumbent hypertension induced by fludrocortisone was studied in 7 patients with orthostatic hypotension. All showed increases in blood pressure in the recumbent and standing positions, and hypertensive levels were achieved on recumbency in 4 of them. Hypertensive retinopathy developed in 2 patients and cardiomegaly in one. Initial blood pressure elevations were associated with sodium retention and plasma volume expansion. However, with long term treatment, plasma volume decreased to control levels despite further blood pressure increases. Treatment did not affect plasma levels of catecholamines but did enhance pressor responsiveness to infused norepinephrine in some subjects. Hemodynamic studies indicated that hypertension in the recumbent position was related to increases in total peripheral vascular resistance and not to changes in cardiac output. Clinically, hypertension in the recumbent position is an important risk of fludrocortisone treatment in patients with orthostatic hypotension. This unusual model of chronic mineralocorticoid induced hypertension is not volume dependent but is related to increased peripheral vascular resistance.
For more Drug Warnings (Complete) data for FLUDROCORTISONE (13 total), please visit the HSDB record page.

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Pharmacodynamics
Fludrocortisone is a synthetic mineralocorticoid used to replace endogenous [aldosterone] in conditions resulting in missing or inadequate endogenous synthesis. It acts on the kidneys to increase both sodium reabsorption and potassium excretion. As its effects are exerted at the transcriptional level, a single dose of fludrocortisone may work over the course of 1-2 days despite a relatively short plasma half-life. Like other systemic corticosteroids, fludrocortisone may mask signs of infection by depressing the normal immune response - infections occurring during fludrocortisone therapy should be promptly treated with appropriate antimicrobial therapy.

C21H29FO5

380.45

380.199

127-31-1

Fludrocortisone acetate;514-36-3;Fludrocortisone-d5;Fludrocortisone-d2

31378

White to off-white solid powder

1.7

3

6

2

27

734

7

C[C@@]12[C@](C(CO)=O)(O)CC[C@@]1([H])[C@]3([H])CCC4=CC(CC[C@]4(C)[C@@]3(F)[C@@H](O)C2)=O

AAXVEMMRQDVLJB-BULBTXNYSA-N

InChI=1S/C21H29FO5/c1-18-7-5-13(24)9-12(18)3-4-15-14-6-8-20(27,17(26)11-23)19(14,2)10-16(25)21(15,18)22/h9,14-16,23,25,27H,3-8,10-11H2,1-2H3/t14-,15-,16-,18-,19-,20-,21-/m0/s1

(8S,9R,10S,11S,13S,14S,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one

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 : ~100 mg/mL (~262.85 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.57 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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