Fexofenadine

Fexofenadine
Systematic (IUPAC) name
(RS)- 2-[4-[1-Hydroxy- 4-[4-(hydroxy- diphenyl- methyl) - 1-piperidyl]butyl]phenyl]- 2-methyl- propanoic acid
Clinical data
Trade names Allegra
AHFS/Drugs.com monograph
MedlinePlus a697035
Licence data US FDA:link
Pregnancy cat. B2(AU) C(US)
Legal status Unscheduled (AU) OTC (CA) POM (UK) OTC (US)
Routes Oral
Pharmacokinetic data
Bioavailability 30-41%[1]
Protein binding 60-70%
Metabolism Hepatic (5% of dose)
Half-life 14.4 hours
Excretion Feces (~80%) and urine (~11%) as unchanged drug
Identifiers
CAS number 83799-24-0 Y
ATC code R06AX26
PubChem CID 3348
DrugBank APRD00349
ChemSpider 3231 Y
UNII E6582LOH6V Y
KEGG D07958 Y
ChEBI CHEBI:5050 Y
ChEMBL CHEMBL914 Y
Chemical data
Formula C32H39NO4 
Mol. mass 501.656
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Fexofenadine (trade names Allegra, Telfast, Fastofen, Tilfur, Vifas, Telfexo, Allerfexo) is an antihistamine drug used in the treatment of hayfever and similar allergy symptoms. It was developed as a successor of and alternative to terfenadine (trade names include Triludan and Seldane), an antihistamine that caused QT interval prolongation, potentially leading to cardiac arrhythmia. Fexofenadine, like other second- and third-generation antihistamines, does not readily cross the blood-brain barrier, and so causes less drowsiness than first-generation histamine-receptor antagonists. It works by being an antagonist to the H1 receptor.[2]

It has been described as both a second-generation[3] and third-generation antihistamine.[4]

Contents

Indications

Fexofenadine is indicated for the relief from physical symptoms associated with seasonal allergic rhinitis and treatment of chronic urticaria.[5] It is not a therapeutic drug and does not cure but rather prevents the aggravation of rhinitis and urticaria and reduces the severity of the symptoms associated with those conditions, providing much relief from repeated sneezing, runny nose, itchy eyes and general body fatigue.[6][7]

Dosage

Fexofenadine is not well examined for children under 12 years.[6]

Dosage forms

Side effects

The most common side effects are headache, nausea, dizziness, drowsiness and sleepiness; nervousness nightmares and frequent coughing are seen in less than 1% of patients. In studies, all of these effects occurred with similar frequencies as under placebo.[6][7]

Overdose

Reports of fexofenadine overdose are infrequent, and because of this, the effects are not well established. No deaths occurred in testing on mice, at 5000 mg/kg body weight, which is one-hundred and ten times the maximum recommended dose for an adult human. Further research shows no deaths in rats at the same concentration, which equates four hundred times the recommended dose in an adult human.

Research on humans ranges from a single 800 mg dose, to a twice-daily 690 mg dose for a month, with no clinically significant adverse effects, when compared to a placebo.[6]

Mechanism of action

Fexofenadine is a second-generation selectively peripheral H1-blocker of the GI tract, large blood vessels, and bronchial smooth muscle. Blockage prevents the activation of the H1 receptors by histamine, preventing the symptoms associated with allergies from occurring. Fexofenadine cannot cross the blood-brain barrier and therefore does not cause drowsiness. It also exhibits no anticholinergic, antidopaminergic, alpha1-adrenergic, or beta-adrenergic-receptor-blocking effects.[11]

Pharmacokinetics

After oral application, about one-third of the drug is absorbed into the bloodstream. Maximum plasma concentrations are reached after one to three hours. Fexofenadine is effective from one hour to 24 hours after application, with maximum effectiveness after six hours.[7]

Only a small percentage is metabolized in the liver, mainly to the methyl ester and to azacyclonol; both are pharmacologically irrelevant. Most of the substance is eliminated unchanged via the feces (80%) and urine (11–12%).[7]

Interactions

Erythromycin and ketoconazole increase the plasma levels of fexofenadine two- to threefold without influencing the QT interval. The reason for this effect is not well understood and could be caused by increased absorption or reduced gastrointestinal or biliary secretion.[7][12]

Antacids containing aluminium or magnesium reduce the absorption of fexofenadine.[7] Fexofenadine is not to be taken with fruit juices, as decrease of the absorption of the drug could be effected.[13] Grapefruit juices can significantly reduce plasma concentration of fexofenadine.

While St. John's Wort (hypericum perforatum) and its preparations do interact with fexofenadine, since fexofenadine is a P-glycoprotein substrate and hypericum is an inducer, this interaction is deemed "unlikely to cause problems" - see St John's Wort Interactions table.

History

The older antihistaminic agent terfenadine was found to metabolize into the related carboxylic acid, fexofenadine. Fexofenadine was found to retain all of the biological activity of its parent while giving fewer adverse reactions in patients, so terfenadine was replaced in the market by its metabolite.[14] Fexofenadine was originally synthesized in 1993 by Massachusetts-based biotechnology company Sepracor, which then sold the development rights to Hoechst Marion Roussel (now part of Sanofi-Aventis), and was later approved by the Food and Drug Administration (FDA) in 1996. AMRI holds the patents to the intermediates and production of fexofenadine HCl along with Roussel. Since that time, it has achieved blockbuster drug status with global sales of $1.87B USD in 2004 (with $1.49B USD coming from the United States). AMRI received royalty payments from Aventis that enabled the growth of AMRI.

On January 25, 2011, the FDA approved over-the-counter sales of fexofenadine in the United States, and Sanofi-Aventis' version became available on March 4, 2011.[15]

Synthesis

Fexofenadine may be synthesized as shown from piperidine-4-carboxylate ester and 4-bromophenylacetonitrile.[14][16]

To produce the piperidine piece, two phenyl groups are first introduced using a Grignard reaction on the ester, giving a tertiary alcohol. The amine group is then alkylated with a protected aldehyde, then the aldehyde is recovered by deprotection with acid. The remaining piece of the molecule is produced by a double alkylation by iodomethane of the carbanion derived from the nitrile. The nitrile group is then hydrolyzed to a carboxylic acid. The aryl bromide is then lithiated to produce the organolithium compound, which can be coupled with the aldehyde piece to give (after workup) fexofenadine.

References

  1. ^ Lappin G, Shishikura Y, Jochemsen R, Weaver RJ, Gesson C, Houston B, Oosterhuis B, Bjerrum OJ, Rowland M, Garner C (May 2010). "Pharmacokinetics of fexofenadine: evaluation of a microdose and assessment of absolute oral bioavailability". Eur J Pharm Sci 40 (2): 125–31. doi:10.1016/j.ejps.2010.03.009. PMID 20307657. 
  2. ^ Katagiri, K.; Arakawa, S.; Hatano, Y.; Fujiwara, S. (2006). "Fexofenadine, an H1-receptor antagonist, partially but rapidly inhibits the itch of contact dermatitis induced by diphenylcyclopropenone in patients with alopecia areata". The Journal of Dermatology 33 (2): 75. doi:10.1111/j.1346-8138.2006.00017.x. PMID 16556272.  edit
  3. ^ Dicpinigaitis PV, Gayle YE (November 2003). "Effect of the second-generation antihistamine, fexofenadine, on cough reflex sensitivity and pulmonary function". British journal of clinical pharmacology 56 (5): 501–4. doi:10.1046/j.1365-2125.2003.01902.x. PMC 1884387. PMID 14651723. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1884387. 
  4. ^ Vena GA, Cassano N, Filieri M, Filotico R, D'Argento V, Coviello C (2002). "Fexofenadine in chronic idiopathic urticaria: a clinical and immunohistochemical evaluation". Int J Immunopathol Pharmacol 15 (3): 217–24. PMID 12575922. 
  5. ^ March 22, 2011 (2002-11-07). "fexofenadine (Allegra) - drug class, medical uses, medication side effects, and drug interactions by". Medicinenet.com. http://www.medicinenet.com/fexofenadine/article.htm. Retrieved 2011-03-22. 
  6. ^ a b c d Haberfeld, H, ed (2010) (in German). Austria-Codex (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag. 
  7. ^ a b c d e f Dinnendahl, V, Fricke, U, ed (2010) (in German). Arzneistoff-Profile. 2 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-98-46-3. 
  8. ^ a b c Allegra (fexofenadine hydrochloride) tablets, ODT, and oral suspension package insert. Bridgewater, NJ: Sanofi-Aventis; 2008 Dec.
  9. ^ Allegra D-12 Hour (fexofenadine hcl and pseudoephedrine hcl) tablets, extended release package insert. Bridgewater, NJ: Sanofi-Aventis; 2009 Dec.
  10. ^ Allegra-D 24 Hour (fexofenadine hcl and pseudoephedrine hcl) tablets, extended release package insert. Bridgewater, NJ: Sanofi-Aventis; 2009 Dec.
  11. ^ "Fexofenadine", DrugBank, accessed June 13, 2011.
  12. ^ Klopp, T, ed (2010) (in German). Arzneimittel-Interaktionen (2010/2011 ed.). Arbeitsgemeinschaft für Pharmazeutische Information. ISBN 978-3-85200-207-1. 
  13. ^ Kamath, AV; Yao, M; Zhang, Y; Chong, S (2005). "Effect of fruit juices on the oral bioavailability of fexofenadine in rats". Journal of pharmaceutical sciences 94 (2): 233–9. doi:10.1002/jps.20231. PMID 15570603. 
  14. ^ a b Daniel Lednicer (1999). The Organic Chemistry of Drug Synthesis. 6. New York: Wiley Interscience. pp. 38–40. ISBN 0-471-24510-0. 
  15. ^ "Allegra | FAQs". Sanofi-Aventis. http://www.allegra.com/faqs.aspx. Retrieved 5 July 2011. 
  16. ^ Kawai, SH; Hambalek, RJ; Just, G (May 1994). "A facile synthesis of an oxidation product of terfenadine". J. Org. Chem. 59 (9): 2620–22. doi:10.1021/jo00088a056. 
  • Biological effects: Rampe, D; Wible, B; Brown, AM; Dage, RC (December 1993). "Effects of terfenadine and its metabolites on a delayed rectifier K+ channel cloned from human heart". Mol. Pharmacol. 44 (6): 1240–5. PMID 8264561. 

External links