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Identification
NameAstemizole
Accession NumberDB00637  (APRD00585)
TypeSmall Molecule
GroupsApproved, Withdrawn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 It was withdrawn from market by the manufacturer in 1999 due to the potential to cause arrhythmias at high doses, especially when when taken with CYP inhibitors or grapefruit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
Synonyms
1-(P-Fluorobenzyl)-2-((1-(2-(P-methoxyphenyl)ethyl)piperid-4-yl)amino)benzimidazole
1-(P-Fluorobenzyl)-2-((1-(P-methoxyphenethyl)-4-piperidyl)amino)benzimidazole
Astemison
Astemizol
Astemizol
Astémizole
Astemizolum
External Identifiers
  • BRN 4830190
  • R43512
  • UNII-7HU6337315
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Hismanal - Tab 10mgtablet10 mgoralJohnson & Johnson Merck Consumer Pharmaceuticals Of Canada1997-01-211999-03-04Canada
Hismanal Suspension 2mg/mlsuspension2 mgoralJanssen Pharmaceutica, Division Of Janssen Ortho Inc.1984-12-311997-08-12Canada
Hismanal Tab 10mgtablet10 mgoralJanssen Pharmaceutica, Division Of Janssen Ortho Inc.1984-12-311997-08-12Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AcemizLupin
AlerkinIncobra
AstesenSenosiain
HismanalJanssen
HistalongBiofarma
LergibrumizolBruluart
StemizCadila HC
Brand mixturesNot Available
SaltsNot Available
Categories
UNII7HU6337315
CAS number68844-77-9
WeightAverage: 458.5703
Monoisotopic: 458.248189839
Chemical FormulaC28H31FN4O
InChI KeyInChIKey=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)
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=CC=CC=C3N2CC2=CC=C(F)C=C2)C=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as benzimidazoles. These are organic compounds containing a benzene ring fused to an imidazole ring (five member ring containing a nitrogen atom, 4 carbon atoms, and two double bonds).
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzimidazoles
Sub ClassNot Available
Direct ParentBenzimidazoles
Alternative Parents
Substituents
  • Phenethylamine
  • Benzimidazole
  • Methoxybenzene
  • Phenylmethylamine
  • Phenol ether
  • Anisole
  • Aralkylamine
  • Secondary aliphatic/aromatic amine
  • Halobenzene
  • Fluorobenzene
  • 4-aminopiperidine
  • Alkyl aryl ether
  • Benzenoid
  • Piperidine
  • N-substituted imidazole
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl fluoride
  • Aminoimidazole
  • Heteroaromatic compound
  • Imidazole
  • Azole
  • Tertiary aliphatic amine
  • Tertiary amine
  • Azacycle
  • Secondary amine
  • Ether
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationAstemizole 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.
PharmacodynamicsAstemizole 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 actionAstemizole 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.
Related Articles
AbsorptionRapidly absorbed from the gastrointestinal tract.
Volume of distributionNot Available
Protein binding96.7%
Metabolism

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

SubstrateEnzymesProduct
Astemizole
desmethylastemizoleDetails
Route of eliminationNot Available
Half life1 day
ClearanceNot Available
ToxicityLD50=2052mg/kg in mice
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.765
Caco-2 permeable+0.5217
P-glycoprotein substrateSubstrate0.8162
P-glycoprotein inhibitor IInhibitor0.8563
P-glycoprotein inhibitor IIInhibitor0.8995
Renal organic cation transporterInhibitor0.7708
CYP450 2C9 substrateNon-substrate0.8732
CYP450 2D6 substrateSubstrate0.8918
CYP450 3A4 substrateSubstrate0.6777
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorInhibitor0.8994
CYP450 3A4 inhibitorNon-inhibitor0.5127
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9096
Ames testNon AMES toxic0.6444
CarcinogenicityNon-carcinogens0.9553
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.2847 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.9267
hERG inhibition (predictor II)Inhibitor0.8575
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral10 mg
Suspensionoral2 mg
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point149.1 °CPhysProp
water solubility432 mg/LNot Available
logP5.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0012 mg/mLALOGPS
logP5.92ALOGPS
logP5.39ChemAxon
logS-5.6ALOGPS
pKa (Strongest Basic)8.75ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area42.32 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity135.64 m3·mol-1ChemAxon
Polarizability52.08 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Godelieve Irma Christine Maria Heylen, Cornelus Gerardus Maria Janssen, Jurzak Mirek, Henricus Petrus Martinus Maria Van Assouw, “Radiolabeled astemizole and method of making.” U.S. Patent US07541476, issued June 02, 2009.

US07541476
General References
  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:16723379 ]
  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:16816845 ]
External Links
ATC CodesR06AX11
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (57.2 KB)
Interactions
Drug Interactions
Drug
AtazanavirThe serum concentration of Astemizole can be increased when it is combined with Atazanavir.
BicalutamideThe serum concentration of Astemizole can be increased when it is combined with Bicalutamide.
BoceprevirThe serum concentration of Astemizole can be increased when it is combined with Boceprevir.
CeritinibThe serum concentration of Astemizole can be increased when it is combined with Ceritinib.
ClarithromycinThe serum concentration of Astemizole can be increased when it is combined with Clarithromycin.
CobicistatThe serum concentration of Astemizole can be increased when it is combined with Cobicistat.
DarunavirThe serum concentration of Astemizole can be increased when it is combined with Darunavir.
DelavirdineDelavirdine may increase the arrhythmogenic activities of Astemizole.
FosaprepitantThe serum concentration of Astemizole can be increased when it is combined with Fosaprepitant.
IdelalisibThe serum concentration of Astemizole can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of Astemizole can be increased when it is combined with Indinavir.
ItraconazoleThe serum concentration of Astemizole can be increased when it is combined with Itraconazole.
KetoconazoleKetoconazole may increase the QTc-prolonging activities of Astemizole.
NefazodoneThe serum concentration of Astemizole can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Astemizole can be increased when it is combined with Nelfinavir.
PosaconazoleThe serum concentration of Astemizole can be increased when it is combined with Posaconazole.
RitonavirThe serum concentration of Astemizole can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of Astemizole can be increased when it is combined with Saquinavir.
TelaprevirThe serum concentration of Astemizole can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Astemizole can be increased when it is combined with Telithromycin.
VoriconazoleThe serum concentration of Astemizole can be increased when it is combined with Voriconazole.
Food Interactions
  • Take on an empty stomach, food decreases absorption by 60%.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Histamine receptor activity
Specific Function:
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.
Gene Name:
HRH1
Uniprot ID:
P35367
Molecular Weight:
55783.61 Da
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:8001268 ]
  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:6146346 ]
  3. Kaliner MA, Check WA: Non-sedating antihistamines. Allergy Proc. 1988 Nov-Dec;9(6):649-63. [PubMed:3147222 ]
  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:10597865 ]
  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:10597866 ]
  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:6204835 ]
  7. Krstenansky PM, Cluxton RJ Jr: Astemizole: a long-acting, nonsedating antihistamine. Drug Intell Clin Pharm. 1987 Dec;21(12):947-53. [PubMed:2892659 ]
  8. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function:
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). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are r...
Gene Name:
KCNH2
Uniprot ID:
Q12809
Molecular Weight:
126653.52 Da
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:10376921 ]
  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:10422790 ]
  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:10444235 ]
  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:11575008 ]
  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:15272206 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
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 xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. 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:10597902 ]
  2. 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:11259984 ]
  3. Cvetkovic RS, Goa KL: Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs. 2003;63(8):769-802. [PubMed:12662125 ]
  4. 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:15133245 ]
  5. 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:15684493 ]
  6. 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:10592235 ]
  7. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  8. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Oxygen binding
Specific Function:
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.
Gene Name:
CYP3A5
Uniprot ID:
P20815
Molecular Weight:
57108.065 Da
References
  1. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Oxygen binding
Specific Function:
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.
Gene Name:
CYP3A7
Uniprot ID:
P24462
Molecular Weight:
57525.03 Da
References
  1. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
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.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
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.
Gene Name:
CYP2J2
Uniprot ID:
P51589
Molecular Weight:
57610.165 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
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:12699389 ]
  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:10706423 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11