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Identification
Name Terfenadine
Accession Number DB00342 (APRD00606)
Type small molecule
Groups approved, withdrawn
Description

In the U.S., Terfenadine was superseded by fexofenadine in the 1990s due to the risk of cardiac arrhythmia caused by QT interval prolongation.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Ternadin
Salts Not Available
Brand names
Name Company
Aldaban
Allerplus
Cyater
Seldane
Teldane
Teldanex
Terdin
Terfex
Triludan
Brand mixtures Not Available
Categories
  • Antiarrhythmic Agents
  • Anti-Allergic Agents
  • Antihistamines
  • Histamine H1 Antagonists, Non-Sedating
CAS number 50679-08-8
Weight Average: 471.6734
Monoisotopic: 471.313729561
Chemical Formula C32H41NO2
InChI Key InChIKey=GUGOEEXESWIERI-UHFFFAOYSA-N
InChI
InChI=1S/C32H41NO2/c1-31(2,3)26-18-16-25(17-19-26)30(34)15-10-22-33-23-20-29(21-24-33)32(35,27-11-6-4-7-12-27)28-13-8-5-9-14-28/h4-9,11-14,16-19,29-30,34-35H,10,15,20-24H2,1-3H3
Plain Text
IUPAC Name
1-(4-tert-butylphenyl)-4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butan-1-ol
SMILES
CC(C)(C)C1=CC=C(C=C1)C(O)CCCN1CCC(CC1)C(O)(C1=CC=CC=C1)C1=CC=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Diphenylmethanes
Substructures
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Benzene and Derivatives
  • Cumenes and Derivatives
  • Aliphatic and Aryl Amines
  • Alcohols and Polyols
  • Diphenylmethanes
  • Heterocyclic compounds
  • Aromatic compounds
  • Piperidines
Pharmacology
Indication For the treatment of allergic rhinitis, hay fever, and allergic skin disorders.
Pharmacodynamics Terfenadine, an H1-receptor antagonist antihistamine, is similar in structure to astemizole and haloperidol, a butyrophenone antipsychotic. The active metabolite of terfenadine is fexofenadine.
Mechanism of action Terfenadine competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of terfenadine 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, CNS depression is minimal.
Absorption On the basis of a mass balance study using 14C labeled terfenadine the oral absorption of terfenadine was estimated to be at least 70%
Volume of distribution Not Available
Protein binding 70%
Metabolism Hepatic
Route of elimination Not Available
Half life 3.5 hours
Clearance Not Available
Toxicity Mild (e.g., headache, nausea, confusion), but adverse cardiac events including cardiac arrest, ventricular arrhythmias including torsades de pointes and QT prolongation have been reported. LD50=mg/kg (orally in mice)
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers
  • Pharmaceutical Utilization Management Program VA Inc.
  • Pharmedix
  • Veratex Corp.
Dosage forms
Form Route Strength
Tablet Oral
Prices Not Available
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 147 °C PhysProp
water solubility 0.0963 mg/L (at 25 °C) MCFARLAND,JW ET AL. (2001)
logP 7.1 Not Available
Predicted Properties
Property Value Source
water solubility 4.58e-04 g/l ALOGPS
logP 5.89 ALOGPS
logP 6.48 ChemAxon
logS -6 ALOGPS
pKa (strongest acidic) 13.2 ChemAxon
pKa (strongest basic) 9.02 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 43.7 ChemAxon
rotatable bond count 9 ChemAxon
refractivity 146.27 ChemAxon
polarizability 56.45 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00521 Link_out
KEGG Compound C07463 Link_out
PubChem Compound 5405 Link_out
PubChem Substance 46507007 Link_out
ChemSpider 5212 Link_out
BindingDB 50017376 Link_out
Therapeutic Targets Database DAP000102 Link_out
PharmGKB PA451619 Link_out
IUPHAR 2608 Link_out
Guide to Pharmacology 2608 Link_out
Drug Product Database 1913395 Link_out
RxList http://www.rxlist.com/cgi/generic/terfen.htm Link_out
Drugs.com http://www.drugs.com/mtm/terfenadine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Terfenadine Link_out
ATC Codes
  • R06AX12
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS show (72.9 KB)
Interactions
Drug Interactions
Drug Interaction
Acetophenazine Increased risk of cardiotoxicity and arrhythmias
Amiodarone Increased risk of cardiotoxicity and arrhythmias
Amitriptyline Increased risk of cardiotoxicity and arrhythmias
Amoxapine Increased risk of cardiotoxicity and arrhythmias
Amprenavir Increased risk of cardiotoxicity and arrhythmias
Aprepitant Increased risk of cardiotoxicity and arrhythmias
Bepridil Increased risk of cardiotoxicity and arrhythmias
Chlorpromazine Increased risk of cardiotoxicity and arrhythmias
Cimetidine Increased risk of cardiotoxicity and arrhythmias
Cisapride Increased risk of cardiotoxicity and arrhythmias
Clarithromycin Increased risk of cardiotoxicity and arrhythmias
Clomipramine Increased risk of cardiotoxicity and arrhythmias
Delavirdine Increased risk of cardiotoxicity and arrhythmias
Desipramine Increased risk of cardiotoxicity and arrhythmias
Diltiazem Increased risk of cardiotoxicity and arrhythmias
Disopyramide Increased risk of cardiotoxicity and arrhythmias
Doxepin Increased risk of cardiotoxicity and arrhythmias
Efavirenz Increased risk of cardiotoxicity and arrhythmias
Erythromycin Increased risk of cardiotoxicity and arrhythmias
Flecainide Increased risk of cardiotoxicity and arrhythmias
Fluconazole Increased risk of cardiotoxicity and arrhythmias
Fluoxetine Increased risk of cardiotoxicity and arrhythmias
Fluphenazine Increased risk of cardiotoxicity and arrhythmias
Fluvoxamine Increased risk of cardiotoxicity and arrhythmias
Fosamprenavir Increased risk of cardiotoxicity and arrhythmias
Grepafloxacin Increased risk of cardiotoxicity and arrhythmias
Imipramine Increased risk of cardiotoxicity and arrhythmias
Indinavir Increased risk of cardiotoxicity and arrhythmias
Itraconazole Increased risk of cardiotoxicity and arrhythmias
Josamycin Increased risk of cardiotoxicity and arrhythmias
Ketoconazole Increased risk of cardiotoxicity and arrhythmias
Mesoridazine Increased risk of cardiotoxicity and arrhythmias
Methdilazine Increased risk of cardiotoxicity and arrhythmias
Methotrimeprazine Increased risk of cardiotoxicity and arrhythmias
Mexiletine Increased risk of cardiotoxicity and arrhythmias
Mibefradil Increased risk of cardiotoxicity and arrhythmias
Nefazodone Increased risk of cardiotoxicity and arrhythmias
Nelfinavir Increased risk of cardiotoxicity and arrhythmias
Nicardipine Increased risk of cardiotoxicity and arrhythmias
Nortriptyline Increased risk of cardiotoxicity and arrhythmias
Perphenazine Increased risk of cardiotoxicity and arrhythmias
Posaconazole Contraindicated co-administration
Procainamide Increased risk of cardiotoxicity and arrhythmias
Prochlorperazine Increased risk of cardiotoxicity and arrhythmias
Promazine Increased risk of cardiotoxicity and arrhythmias
Promethazine Increased risk of cardiotoxicity and arrhythmias
Propafenone Increased risk of cardiotoxicity and arrhythmias.
Propericiazine Increased risk of cardiotoxicity and arrhythmias
Propiomazine Increased risk of cardiotoxicity and arrhythmias
Protriptyline Increased risk of cardiotoxicity and arrhythmias
Quinidine Increased risk of cardiotoxicity and arrhythmias
Quinine Increased risk of cardiotoxicity and arrhythmias
Quinupristin This combination presents an increased risk of toxicity
Ritonavir Increased risk of cardiotoxicity and arrhythmias
Saquinavir Increased risk of cardiotoxicity and arrhythmias
Sotalol Increased risk of cardiotoxicity and arrhythmias
Sparfloxacin Increased risk of cardiotoxicity and arrhythmias
Telavancin Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Telithromycin Increased risk of cardiotoxicity and arrhythmias
Thiethylperazine Increased risk of cardiotoxicity and arrhythmias
Thioridazine Increased risk of cardiotoxicity and arrhythmias
Tipranavir Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Terfenadine. Concomitant therapy is contraindicated.
Tocainide Increased risk of cardiotoxicity and arrhythmias
Trifluoperazine Increased risk of cardiotoxicity and arrhythmias
Triflupromazine Increased risk of cardiotoxicity and arrhythmias
Trimeprazine Increased risk of cardiotoxicity and arrhythmias
Trimipramine Increased risk of cardiotoxicity and arrhythmias
Troleandomycin Increased risk of cardiotoxicity and arrhythmias
Verapamil Increased risk of cardiotoxicity and arrhythmias
Voriconazole Increased risk of cardiotoxicity and arrhythmias
Food Interactions Not Available
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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Kishimoto W, Hiroi T, Sakai K, Funae Y, Igarashi T: Metabolism of epinastine, a histamine H1 receptor antagonist, in human liver microsomes in comparison with that of terfenadine. Res Commun Mol Pathol Pharmacol. 1997 Dec;98(3):273-92. Pubmed
  3. 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
  4. Wood-Baker R, Smith R, Holgate ST: A double-blind, placebo controlled study of the effect of the specific histamine H1-receptor antagonist, terfenadine, in chronic severe asthma. Br J Clin Pharmacol. 1995 Jun;39(6):671-5. Pubmed
  5. Phillips GD, Polosa R, Holgate ST: The effect of histamine-H1 receptor antagonism with terfenadine on concentration-related AMP-induced bronchoconstriction in asthma. Clin Exp Allergy. 1989 Jul;19(4):405-9. Pubmed
  6. Rafferty P, Holgate ST: Terfenadine (Seldane) is a potent and selective histamine H1 receptor antagonist in asthmatic airways. Am Rev Respir Dis. 1987 Jan;135(1):181-4. 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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Gessner G, Zacharias M, Bechstedt S, Schonherr R, Heinemann SH: Molecular determinants for high-affinity block of human EAG potassium channels by antiarrhythmic agents. Mol Pharmacol. 2004 May;65(5):1120-9. Pubmed
  3. Testai L, Cecchetti V, Sabatini S, Martelli A, Breschi MC, Calderone V: Effects of K openers on the QT prolongation induced by HERG-blocking drugs in guinea-pigs. J Pharm Pharmacol. 2010 Jul;62(7):924-30. Pubmed

3. Muscarinic acetylcholine receptor M3

Pharmacological action: unknown
Actions: antagonist

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover

Organism class: human
UniProt ID: P20309 Link_out
Gene: CHRM3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Yasuda SU, Yasuda RP: Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes. Pharmacotherapy. 1999 Apr;19(4):447-51. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inhibitor, inducer

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. Wang RW, Newton DJ, Liu N, Atkins WM, Lu AY: Human cytochrome P-450 3A4: in vitro drug-drug interaction patterns are substrate-dependent. Drug Metab Dispos. 2000 Mar;28(3):360-6. Pubmed
  3. 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
  4. Kishimoto W, Hiroi T, Sakai K, Funae Y, Igarashi T: Metabolism of epinastine, a histamine H1 receptor antagonist, in human liver microsomes in comparison with that of terfenadine. Res Commun Mol Pathol Pharmacol. 1997 Dec;98(3):273-92. Pubmed
  5. Nemeroff CB, DeVane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry. 1996 Mar;153(3):311-20. Pubmed

2. 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.

3. Cytochrome P450 2D6

Actions: substrate, inhibitor

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
  2. Kishimoto W, Hiroi T, Sakai K, Funae Y, Igarashi T: Metabolism of epinastine, a histamine H1 receptor antagonist, in human liver microsomes in comparison with that of terfenadine. Res Commun Mol Pathol Pharmacol. 1997 Dec;98(3):273-92. Pubmed

4. Cytochrome P450 2C9

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. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
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 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.

6. Cytochrome P450 2C8

Actions: 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
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.

7. Cytochrome P450 2J2

Actions: inhibitor

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. Wang EJ, Casciano CN, Clement RP, Johnson WW: Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors. Biochem Biophys Res Commun. 2001 Nov 30;289(2):580-5. Pubmed
  2. 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
  3. Hait WN, Gesmonde JF, Murren JR, Yang JM, Chen HX, Reiss M: Terfenadine (Seldane): a new drug for restoring sensitivity to multidrug resistant cancer cells. Biochem Pharmacol. 1993 Jan 26;45(2):401-6. Pubmed
  4. Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, Roden MM, Belas F, Chaudhary AK, Roden DM, Wood AJ, Wilkinson GR: Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res. 1999 Mar;16(3):408-14. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19