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Identification
Name Astemizole
Accession Number DB00637 (APRD00585)
Type small molecule
Groups approved, withdrawn
Description

Astemizole is a long-acting, non-sedating second generation antihistamine used in the treatment of allergy symptoms. It was withdrawn from market by the manufacturer in 1999 due to the potential to cause arrhythmias at high doses, especially when when taken with CYP inhibitors or grapefruit juice.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Brand names
  • Alermizol
  • Astemisan
  • Astemisol
  • Astemison
  • Hismanal
  • Histamen
  • Histaminos
  • Histazol
  • Kelp
  • Laridal
  • Metodik
  • Nono-Nastizol A
  • Paralergin
  • Retolen
  • Waruzol
Brand name mixtures Not Available
Categories
  • Anti-Allergic Agents
  • Antihistamines
  • Histamine H1 Antagonists, Non-Sedating
CAS number 68844-77-9
Weight Average: 458.5703
Monoisotopic: 458.248189839
Chemical Formula C28H31FN4O
InChI Key InChIKey=GXDALQBWZGODGZ-UHFFFAOYSA-N
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)
Plain Text
IUPAC Name
1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-1,3-benzodiazol-2-amine
SMILES
COC1=CC=C(CCN2CCC(CC2)NC2=NC3=C(C=CC=C3)N2CC2=CC=C(F)C=C2)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenols and Derivatives
  • Benzimidazoles
  • Ethers
  • Phenethylamines
  • Anisoles
Substructures
  • Aliphatic and Aryl Amines
  • Phenols and Derivatives
  • Benzimidazoles
  • Ethers
  • Benzene and Derivatives
  • Halobenzenes
  • Imidazoles
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Cyanamides
  • Aryl Halides
  • Phenyl Esters
  • Piperidines
Pharmacology
Indication Astemizole was indicated for use in the relieving allergy symptoms, particularly rhinitis and conjunctivitis. It has been withdrawn from the market however due to concerns of arrhythmias.
Pharmacodynamics Astemizole is a second generation H1-receptor antagonist. It does not significantly cross the blood brain barrier and therefore does not cause drowsiness or CNS depression at normal doses.
Mechanism of action Astemizole competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of astemizole to H1-receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier and preferentially binds at H1 receptors in the peripehery rather than within the brain, CNS depression is minimal. Astemizole may also act on H3-receptors, producing adverse effects.
Absorption Rapidly absorbed from the gastrointestinal tract.
Volume of distribution Not Available
Protein binding 96.7%
Metabolism

Almost completely metabolized in the liver and primarily excreted in the feces.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 3A4 desmethylastemizole O-demethylation 10 191.82
Route of elimination Not Available
Half life 1 day
Clearance Not Available
Toxicity LD50=2052mg/kg in mice
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms
Form Route Strength
Tablet Oral
Prices Not Available
Patents Not Available
Properties
State solid
Melting point 149.1oC
Experimental Properties
Property Value Source
water solubility 432 mg/L PhysProp
logP 5.8 PhysProp
Predicted Properties
Property Value Source
water solubility 1.20e-03 g/l ALOGPS
logP 5.92 ALOGPS
logP 5.39 ChemAxon Molconvert
logS -5.58 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 4 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 42.32 ChemAxon Molconvert
rotatable bond count 8 ChemAxon Molconvert
refractivity 135.64 ChemAxon Molconvert
polarizability 52.08 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Wang X, Hockerman GH, Green HW 3rd, Babbs CF, Mohammad SI, Gerrard D, Latour MA, London B, Hannon KM, Pond AL: Merg1a K+ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway. FASEB J. 2006 Jul;20(9):1531-3. Epub 2006 May 24. Pubmed
  2. Chong CR, Chen X, Shi L, Liu JO, Sullivan DJ Jr: A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol. 2006 Aug;2(8):415-6. Epub 2006 Jul 2. Pubmed
External Links
Resource Link
KEGG Drug D00234 Link_out
KEGG Compound C06832 Link_out
PubChem Compound 2247 Link_out
PubChem Substance 46508569 Link_out
ChemSpider 2160 Link_out
BindingDB 24226 Link_out
ChEBI 2896 Link_out
ChEMBL 2896 Link_out
Therapeutic Targets Database DAP000326 Link_out
PharmGKB PA448498 Link_out
Drug Product Database 2182912 Link_out
RxList http://www.rxlist.com/cgi/generic/astem.htm Link_out
Drugs.com http://www.drugs.com/mtm/astemizole.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Astemizole Link_out
ATC Codes
  • R06AX11
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS show (57.2 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take on an empty stomach, food decreases absorption by 60%.
Targets

1. Histamine H1 receptor

Pharmacological action: yes
Actions: antagonist

In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system

Organism class: human
UniProt ID: P35367 Link_out
Gene: HRH1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Salata JJ, Jurkiewicz NK, Wallace AA, Stupienski RF 3rd, Guinosso PJ Jr, Lynch JJ Jr: Cardiac electrophysiological actions of the histamine H1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine. Circ Res. 1995 Jan;76(1):110-9. Pubmed
  2. Howarth PH, Emanuel MB, Holgate ST: Astemizole, a potent histamine H1-receptor antagonist: effect in allergic rhinoconjunctivitis, on antigen and histamine induced skin weal responses and relationship to serum levels. Br J Clin Pharmacol. 1984 Jul;18(1):1-8. Pubmed
  3. Kaliner MA, Check WA: Non-sedating antihistamines. Allergy Proc. 1988 Nov-Dec;9(6):649-63. Pubmed
  4. Cavero I, Mestre M, Guillon JM, Heuillet E, Roach AG: Preclinical in vitro cardiac electrophysiology: a method of predicting arrhythmogenic potential of antihistamines in humans? Drug Saf. 1999;21 Suppl 1:19-31; discussion 81-7. Pubmed
  5. Llenas J, Cardelus I, Heredia A, de Mora F, Gristwood RW: Cardiotoxicity of histamine and the possible role of histamine in the arrhythmogenesis produced by certain antihistamines. Drug Saf. 1999;21 Suppl 1:33-8; discussion 81-7. Pubmed
  6. Richards DM, Brogden RN, Heel RC, Speight TM, Avery GS: Astemizole. A review of its pharmacodynamic properties and therapeutic efficacy. Drugs. 1984 Jul;28(1):38-61. Pubmed
  7. Krstenansky PM, Cluxton RJ Jr: Astemizole: a long-acting, nonsedating antihistamine. Drug Intell Clin Pharm. 1987 Dec;21(12):947-53. Pubmed
  8. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Potassium voltage-gated channel subfamily H member 2

Pharmacological action: unknown
Actions: inhibitor

Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoform 3 has no channel activity by itself, but modulates channel characteristics when associated with isoform 1

Organism class: human
UniProt ID: Q12809 Link_out
Gene: KCNH2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou Z, Vorperian VR, Gong Q, Zhang S, January CT: Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. J Cardiovasc Electrophysiol. 1999 Jun;10(6):836-43. Pubmed
  2. Chachin M, Katayama Y, Yamada M, Horio Y, Ohmura T, Kitagawa H, Uchida S, Kurachi Y: Epinastine, a nonsedating histamine H1 receptor antagonist, has a negligible effect on HERG channel. Eur J Pharmacol. 1999 Jun 25;374(3):457-60. Pubmed
  3. Taglialatela M, Castaldo P, Pannaccione A, Giorgio G, Genovese A, Marone G, Annunziato L: Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity. Clin Exp Allergy. 1999 Jul;29 Suppl 3:182-9. Pubmed
  4. Grzelewska-Rzymowska I, Pietrzkowicz M, Gorska M: [The effect of second generation histamine antagonists on the heart] Pneumonol Alergol Pol. 2001;69(3-4):217-26. Pubmed
  5. Chiu PJ, Marcoe KF, Bounds SE, Lin CH, Feng JJ, Lin A, Cheng FC, Crumb WJ, Mitchell R: Validation of a [3H]astemizole binding assay in HEK293 cells expressing HERG K+ channels. J Pharmacol Sci. 2004 Jul;95(3):311-9. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Sweta N. Parikh, et al. Microsomes: Characterization and Inter-Individual Variability Among Donors. Source
  3. Nicolas JM, Whomsley R, Collart P, Roba J: In vitro inhibition of human liver drug metabolizing enzymes by second generation antihistamines. Chem Biol Interact. 1999 Nov 15;123(1):63-79. Pubmed
  4. Matsumoto S, Yamazoe Y: Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine. Br J Clin Pharmacol. 2001 Feb;51(2):133-42. Pubmed
  5. Cvetkovic RS, Goa KL: Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs. 2003;63(8):769-802. Pubmed
  6. Goto A, Adachi Y, Inaba A, Nakajima H, Kobayashi H, Sakai K: Identification of human p450 isoforms involved in the metabolism of the antiallergic drug, oxatomide, and its inhibitory effect on enzyme activity. Biol Pharm Bull. 2004 May;27(5):684-90. Pubmed
  7. Goto A, Ueda K, Inaba A, Nakajima H, Kobayashi H, Sakai K: Identification of human P450 isoforms involved in the metabolism of the antiallergic drug, oxatomide, and its kinetic parameters and inhibition constants. Biol Pharm Bull. 2005 Feb;28(2):328-34. Pubmed
  8. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed
  9. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A5

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 3A7

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

4. Cytochrome P450 2D6

Actions: substrate

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 2J2

Actions: substrate

This enzyme metabolizes arachidonic acid predominantly via a NADPH-dependent olefin epoxidation to all four regioisomeric cis-epoxyeicosatrienoic acids. One of the predominant enzymes responsible for the epoxidation of endogenous cardiac arachidonic acid pools

UniProt ID: P51589 Link_out
Gene: CYP2J2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. Pubmed
  2. Ishikawa M, Fujita R, Takayanagi M, Takayanagi Y, Sasaki K: Reversal of acquired resistance to doxorubicin in K562 human leukemia cells by astemizole. Biol Pharm Bull. 2000 Jan;23(1):112-5. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on October 20, 2011 13:16

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.