Astemizole

Last updated
Astemizole
Astemizole.svg
Clinical data
AHFS/Drugs.com Multum Consumer Information
MedlinePlus a600034
Pregnancy
category
Routes of
administration 		Oral
ATC code
Legal status
Legal status
  • Withdrawn
Pharmacokinetic data
Protein binding ~96%
Metabolism Hepatic (CYP3A4) [1]
Elimination half-life 24 hours
Excretion Fecal
Identifiers
  • 1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidyl]benzoimidazol-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.065.837 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C28H31FN4O
Molar mass 458.581 g·mol−1
3D model (JSmol)
  • Fc1ccc(cc1)Cn2c5ccccc5nc2NC4CCN(CCc3ccc(OC)cc3)CC4
  • InChI=1S/C28H31FN4O/c1-34-25-12-8-21(9-13-25)14-17-32-18-15-24(16-19-32)30-28-31-26-4-2-3-5-27(26)33(28)20-22-6-10-23(29)11-7-22/h2-13,24H,14-20H2,1H3,(H,30,31) Yes check.svgY
  • Key:GXDALQBWZGODGZ-UHFFFAOYSA-N Yes check.svgY
   (verify)

Astemizole (marketed under the brand name Hismanal, developmental code R43512) was a second-generation antihistamine drug that has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977. It was withdrawn from the market globally in 1999 because of rare but potentially fatal side effects (QTc interval prolongation and related arrhythmias due to hERG channel blockade). [2] [3]

Contents

Pharmacology

Astemizole is a histamine H1-receptor antagonist. It has anticholinergic and antipruritic effects.

Astemizole is rapidly absorbed from the gastrointestinal tract and competitively binds to histamine H1 receptor sites in the gastrointestinal tract, uterus, blood vessels, and bronchial muscle. This suppresses the formation of edema and pruritus (caused by histamine).

Despite some earlier reports that astemizole does not cross the blood–brain barrier, several studies [4] [5] have shown high permeability and high binding to protein folds associated with Alzheimer's.

Astemizole may also act on histamine H3 receptors, thereby producing adverse effects.[ citation needed ]

Astemizole does also act as FIASMA (functional inhibitor of acid sphingomyelinase). [6]

Astemizole has been researched as a treatment for Creutzfeldt-Jakob Disease (CJD). [7]

Like many carbendazim-derived benzimidazoles, it has been reported to interact with tubulin and inhibit its polymerization. [8]

Toxicity

Astemizole has an oral LD50 of approximately 2052 mg/kg (in mice).

References

  1. ↑ Matsumoto S, Yamazoe Y (February 2001). "Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine". British Journal of Clinical Pharmacology. 51 (2): 133–142. doi:10.1111/j.1365-2125.2001.01292.x. PMC   2014443 . PMID   11259984.
  2. ↑ Zhou Z, Vorperian VR, Gong Q, Zhang S, January CT (June 1999). "Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole". Journal of Cardiovascular Electrophysiology. 10 (6): 836–843. doi:10.1111/j.1540-8167.1999.tb00264.x. PMID   10376921. S2CID   25655101.
  3. ↑ Charles O, Onakpoya I, Benipal S, Woods H, Bali A, Aronson JK, et al. (2019). "Withdrawn medicines included in the essential medicines lists of 136 countries". PLOS ONE. 14 (12): e0225429. Bibcode:2019PLoSO..1425429C. doi: 10.1371/journal.pone.0225429 . PMC   6887519 . PMID   31791048.{{cite journal}}: CS1 maint: article number as page number (link)
  4. ↑ Rojo LE, Alzate-Morales J, Saavedra IN, Davies P, Maccioni RB (2010). "Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease". Journal of Alzheimer's Disease. 19 (2). IOS Press: 573–589. doi:10.3233/JAD-2010-1262. PMC   2951486 . PMID   20110603.
  5. ↑ Di L, Kerns EH, Fan K, McConnell OJ, Carter GT (March 2003). "High throughput artificial membrane permeability assay for blood-brain barrier". European Journal of Medicinal Chemistry. 38 (3): 223–232. doi:10.1016/S0223-5234(03)00012-6. PMID   12667689.
  6. ↑ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, et al. (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLOS ONE. 6 (8): e23852. Bibcode:2011PLoSO...623852K. doi: 10.1371/journal.pone.0023852 . PMC   3166082 . PMID   21909365.{{cite journal}}: CS1 maint: article number as page number (link)
  7. ↑ Karapetyan YE, Sferrazza GF, Zhou M, Ottenberg G, Spicer T, Chase P, et al. (April 2013). "Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents". Proceedings of the National Academy of Sciences of the United States of America. 110 (17): 7044–7049. Bibcode:2013PNAS..110.7044K. doi: 10.1073/pnas.1303510110 . PMC   3637718 . PMID   23576755.
  8. ↑ Baksheeva VE, La Rocca R, Allegro D, Derviaux C, Pasquier E, Roche P, Morelli X, Devred F, Golovin AV, Tsvetkov PO (2025). "NanoDSF Screening for Anti-tubulin Agents Uncovers New Structure–Activity Insights". Journal of Medicinal Chemistry. 68 (16): 17485–17498. doi:10.1021/acs.jmedchem.5c01008. PMC   12406199 . PMID   40815226.
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