Flunisolide

Absorption

Absorbed rapidly

Description

Flunisolide hemihydrate is administered by inhalation from metered aerosol and used in the management of asthma.

Chemical properties

White Solid

Originator

Syntaris,Syntex,UK,1978

The Uses of Flunisolide

Synthetic fluorinated corticosteroid related to Prednisolone (P703740). Antiasthmatic.

Indications

For the maintenance treatment of asthma as a prophylactic therapy.

Background

Flunisolide (marketed as AeroBid, Nasalide, Nasarel) is a corticosteroid with anti-inflammatory actions. It is often prescribed as treatment for allergic rhinitis and its principle mechanism of action involves activation of glucocorticoid receptors.

What are the applications of Application

Flunisolide-d6 is a fluorinated steroid

Definition

ChEBI: Flunisolide is a fluorinated steroid, a cyclic ketal, a 20-oxo steroid, a 21-hydroxy steroid, an 11beta-hydroxy steroid, a 3-oxo-Delta(1),Delta(4)-steroid and a primary alpha-hydroxy ketone. It has a role as an immunosuppressive agent, an anti-inflammatory drug and an anti-asthmatic drug.

Manufacturing Process

(a) Preparation of 6α-fluoro-16α-hydroxyprednisolone: 1.9 liters of whole mash containing 400 mg of 6α-fluoroprednisolone (6α-fluoro-11β,17α,21- trihydroxy-1,4-pregnadiene-3,20-dione) acted upon by Streptomyces roseochromogenus AE-751 (or Waksman No. 3689) is filtered and the filtrate extracted three times with 2 liter portions of ethyl acetate. The mycelium is extracted with 500 ml of ethyl acetate and the mixture filtered. The combined ethyl acetate extracts are washed with 200 ml of water and concentrated to a residue. The residue is subjected to partition chromatograph using a 200 g column of diatomaceous earth moistened with the lower phase of an equilibrated solvent system composed of 1 volume of water, 5 volumes of dioxane, and 3 volumes of cyclohexane. The upper phase is used to develop the column and the activity of the eluent is followed by measuring the ultraviolet absorbance at 240 mμ. The cuts containing most of the activity are concentrated to a syrupy residue and triturated with acetone. Crystals (25 mg) form and recrystallization gives a product with a MP of 226°C to 230°C.
(b) Preparation of 16α,17α-isopropylidenedioxy-6α-fluoro-1,4-pregnadiene- 11β,21-diol-3,20-dione: 15 mg of crystalline 6α-fluoro-11β,16α,17α,21- tetrahydroxy-1,4-pregnadiene-3,20-dione [6α-fluoro-16α-hydroxyprednisolone described in US Patent 2,838,546 and prepared as described in (a) above] is dissolved in 2 ml of acetone and 0.02 ml of 70% perchloric acid is added. The solution is allowed to stand 1 hour. Then 0.5 ml of saturated sodium bicarbonate solution is added and the solution concentrated under reduced pressure to about 1 ml. The solution is allowed to stand overnight and the crystals which form are filtered, washed with ether and recrystallized from acetone-hexane. The crystals are the 16α,17α-isopropylidene derivative of 6α- fluoro-16α-hydroxyprednisolone.

brand name

Aerobid (Roche); Aerospan Hfa (Forest); Nasalide (IVAX); Nasarel (IVAX).

Therapeutic Function

Antiinflammatory

General Description

The portion of a flunisolide (AeroBid,Nasarel) dose that is swallowed is rapidly converted to the6β-hydroxy metabolite after first-pass metabolism in theliver. The 6β-hydroxy metabolite is approximately as activeas hydrocortisone itself, but the small amount produced usuallyhas limited systemic effects. Water-soluble conjugatesare inactive.

Pharmacokinetics

Flunisolide is a synthetic corticosteroid. It is administered either as an oral metered-dose inhaler for the treatment of asthma or as a nasal spray for treating allergic rhinitis. Corticosteroids are naturally occurring hormones that prevent or suppress inflammation and immune responses. When given as an intranasal spray, flunisolide reduces watery nasal discharge (rhinorrhea), nasal congestion, postnasal drip, sneezing, and itching oat the back of the throat that are common allergic symptoms.

Clinical Use

Flunisolide is an acetone ketal (acetonide) with a 6α-fluoro group and a free C-21 hydroxyl group. The acetonide decreases mineralocorticoid activity, and the 6α-fluoro group increases glucocorticoid activity. It is not a prodrug, because it has the free hydroxyl group at C-21. Flunisolide has approximately 20% of the receptor affinity as budesonide, and approximately 40% of the inhaled dose is systemically bioavailable.

Metabolism

Primarily hepatic, converted to the S beta-OH metabolite.

Metabolism

When administered intranasally or by inhalation, flunisolide is rapidly absorbed from nasal or lung tissue(94). This corticosteroid is efficiently metabolized by the liver to inactive metabolites with no apparent effects on adrenal function with long-term therapy. Flunisolide that is swallowed undergoes extensive first-pass metabolism in the liver, and that which is absorbed directly from the nasopharyngeal mucosa or lung bypasses this initial metabolism. It is not known if the drug undergoes metabolism in the GI tract. Flunisolide is rapidly hydroxylated by CYP3A4 at the 6β position, followed by elimination of the 6α-fluoro group to its more polar 6β-hydroxy metabolite, which attains plasma concentrations that usually are greater than those for flunisolide.