Astemizole

Astemizole
Clinical data
AHFS/Drugs.com	Multum Consumer Information
MedlinePlus	a600034
Pregnancycategory	C (USA);
Routes ofadministration	Oral
ATC code	R06AX11 (WHO) ;
Legal status
Legal status	Withdrawn;
Pharmacokinetic data
Protein binding	~96%
Metabolism	Hepatic (CYP3A4)
Elimination half-life	24 hours
Excretion	Fecal
Identifiers
	IUPAC name 1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidyl]benzoimidazol-2-amine;
CAS Number	68844-77-9 Y;
PubChemCID	2247;
IUPHAR/BPS	2603;
DrugBank	DB00637 Y;
ChemSpider	2160 Y;
UNII	7HU6337315;
KEGG	D00234 Y;
ChEBI	CHEBI:2896 Y;
ChEMBL	ChEMBL296419 Y;
CompTox Dashboard(EPA)	DTXSID9020110;
ECHA InfoCard	100.065.837
Chemical and physical data
Formula	C28H31FN4O
Molar mass	458.581 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES Fc1ccc(cc1)Cn2c5ccccc5nc2NC4CCN(CCc3ccc(OC)cc3)CC4;
	InChI 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) Y; Key:GXDALQBWZGODGZ-UHFFFAOYSA-N Y;
	(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 It was withdrawn from the market globally in 1999 because of rare but potentially fatal side effects (QTc interval prolongation and related arrhythmias due to hERG channel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]

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.

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

^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.
^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.
^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.
^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.
^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.
^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.
^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.
^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.

External links

Statement on Astemizole from Health Canada

[pmid11259984-1] 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.

[pmid10376921-2] 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.

[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.

[pmid18504571-6] 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.

[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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