Fexofenadine

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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 namesAllegra,Axodin
AHFS/Drugs.commonograph
MedlinePlusa697035
Licence dataUS FDA:link
Pregnancy cat.B2 (AU) C (US)
Legal statusUnscheduled (AU) OTC (CA) POM (UK) OTC (US)
RoutesOral
Pharmacokinetic data
Bioavailability30-41%[1]
Protein binding60-70%
MetabolismHepatic (5% of dose)
Half-life14.4 hours
ExcretionFeces (~80%) and urine (~11%) as unchanged drug
Identifiers
CAS number83799-24-0 YesY
ATC codeR06AX26
PubChemCID 3348
DrugBankDB00950
ChemSpider3231 YesY
UNIIE6582LOH6V YesY
KEGGD07958 YesY
ChEBICHEBI:5050 YesY
ChEMBLCHEMBL914 YesY
Chemical data
FormulaC32H39NO4 
Mol. mass501.656
 YesY (what is this?)  (verify)
 
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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 namesAllegra,Axodin
AHFS/Drugs.commonograph
MedlinePlusa697035
Licence dataUS FDA:link
Pregnancy cat.B2 (AU) C (US)
Legal statusUnscheduled (AU) OTC (CA) POM (UK) OTC (US)
RoutesOral
Pharmacokinetic data
Bioavailability30-41%[1]
Protein binding60-70%
MetabolismHepatic (5% of dose)
Half-life14.4 hours
ExcretionFeces (~80%) and urine (~11%) as unchanged drug
Identifiers
CAS number83799-24-0 YesY
ATC codeR06AX26
PubChemCID 3348
DrugBankDB00950
ChemSpider3231 YesY
UNIIE6582LOH6V YesY
KEGGD07958 YesY
ChEBICHEBI:5050 YesY
ChEMBLCHEMBL914 YesY
Chemical data
FormulaC32H39NO4 
Mol. mass501.656
 YesY (what is this?)  (verify)

Fexofenadine (trade names Allegra, Fexidine, Telfast, Fastofen, Tilfur, Vifas, Telfexo, Allerfexo) is an antihistamine pharmaceutical drug used in the treatment of hay fever, allergy symptoms, and urticaria.[2]

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.[3]

It has been variously described as either a second-generation[4] or a third-generation antihistamine.[5]

Indications[edit]

Fexofenadine is indicated for relief from physical symptoms associated with seasonal allergic rhinitis and for treatment of chronic urticaria.[6] 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 relief from repeated sneezing, runny nose, itchy eyes and general body fatigue.[7][8]

Dosage[edit]

Fexofenadine is not well examined for children under 12 years.[7]

Dosage forms[edit]

Side effects[edit]

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.[7][8]

Overdose[edit]

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 (110x) 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.[7]

Mechanism of action[edit]

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 does not readily cross the blood–brain barrier and is therefore unlikely to cause drowsiness. It also exhibits no anticholinergic, antidopaminergic, alpha1-adrenergic, or beta-adrenergic-receptor-blocking effects.[12]

Pharmacokinetics[edit]

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.[8]

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%).[8]

Interactions[edit]

Erythromycin and ketoconazole increase the plasma levels of fexofenadine two- to three-fold 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.[8][13]

Fexofenadine is not to be taken with fruit juice because fruit juice could decrease absorption of the drug.[14] Grapefruit juice can significantly reduce the plasma concentration of fexofenadine.

Antacids containing aluminium or magnesium reduce the absorption of fexofenadine.[8] However antacids containing calcium do not reduce the absorption of fexofenadine. St. John's Wort and its preparations interact with fexofenadine since fexofenadine is a P-glycoprotein substrate and St. John's Wort is an inducer.[medical citation needed]

History[edit]

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.[15] 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.[16]

Synthesis[edit]

Fexofenadine is synthesized in convergent fashion (as shown below) from ethyl piperidine-4-carboxylate and 4-bromophenylacetonitrile.[15][17]

Chemical synthesis of fexofenadine

In the synthesis of fexofenadine, the ultimate and critical bond-formation is the addition of a para-substituted aryl lithium species to a gamma-amino-aldehyde. Ethyl piperidine-4-carboxylate is treated with excess phenylmagnesium bromide to afford (4-piperidinyl)diphenylmethanol. Alkylation of the secondary amine using 2-(3-bromopropyl)-1,3-dioxolane and followed by hydrolysis of the acetal, provides 4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanal.

Separately, 2,2-dimethyl-(p-bromophenyl)acetic acid, prepared in two steps from p-bromophenylacetonitrile, is first deprotonated with NaH and then subjected to lithium halogen exchange, using BuLi to provide the intermediate 2,2-dimethyl-(p-lithiophenyl)acetate salt. This aryl lithium reagent is then reacted with the aforementioned butanal derivative to afford fexofenadine after aqueous workup.

References[edit]

  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. ^ Greaves MW, Tan KT (2007). "Chronic Urticaria: Recent Advances". Clin Rev Allergy Immunol 33 (1–2): 134–143. doi:10.1007/s12016-007-0038-3. PMID 18094952. 
  3. ^ 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): 75–79. doi:10.1111/j.1346-8138.2006.00017.x. PMID 16556272.  edit
  4. ^ 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. 
  5. ^ 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. 
  6. ^ March 22, 2011 (2002-11-07). "fexofenadine (Allegra) - drug class, medical uses, medication side effects, and drug interactions by". Medicinenet.com. Retrieved 2011-03-22. 
  7. ^ a b c d Haberfeld, H, ed. (2010). Austria-Codex (in German) (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag. 
  8. ^ a b c d e f Dinnendahl, V, Fricke, U, ed. (2010). Arzneistoff-Profile (in German) 2 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3. 
  9. ^ a b c Allegra (fexofenadine hydrochloride) tablets, ODT, and oral suspension package insert. Bridgewater, NJ: Sanofi-Aventis; 2008 Dec.
  10. ^ Allegra D-12 Hour (fexofenadine hcl and pseudoephedrine hcl) tablets, extended release package insert. Bridgewater, NJ: Sanofi-Aventis; 2009 Dec.
  11. ^ Allegra-D 24 Hour (fexofenadine hcl and pseudoephedrine hcl) tablets, extended release package insert. Bridgewater, NJ: Sanofi-Aventis; 2009 Dec.
  12. ^ "Fexofenadine", DrugBank, accessed June 13, 2011.
  13. ^ Klopp, T, ed. (2010). Arzneimittel-Interaktionen (in German) (2010/2011 ed.). Arbeitsgemeinschaft für Pharmazeutische Information. ISBN 978-3-85200-207-1. 
  14. ^ 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. 
  15. ^ a b Daniel Lednicer (1999). The Organic Chemistry of Drug Synthesis 6. New York: Wiley Interscience. pp. 38–40. ISBN 0-471-24510-0. 
  16. ^ "Allegra | FAQs". Sanofi-Aventis. Retrieved 5 July 2011. 
  17. ^ 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[edit]