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targets (2) enzymes (2)
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Identification
Name Bisoprolol
Accession Number DB00612 (APRD00257)
Type small molecule
Groups approved
Description

Bisoprolol is a cardioselective β1-adrenergic blocking agent used for secondary prevention of myocardial infarction (MI), heart failure, angina pectoris and mild to moderate hypertension. Bisoprolol is structurally similar to metoprolol, acebutolol and atenolol in that it has two substituents in the para position of the benzene ring. The β1-selectivity of these agents is thought to be due in part to the large substituents in the para position. At lower doses (less than 20 mg daily), bisoprolol selectively blocks cardiac β1-adrenergic receptors with little activity against β2-adrenergic receptors of the lungs and vascular smooth muscle. Receptor selectivity decreases with daily doses of 20 mg or greater. Unlike propranolol and pindolol, bisoprolol does not exhibit membrane-stabilizing or sympathomimetic activity. Bisoprolol possesses a single chiral centre and is administered as a racemic mixture. Only l-bisoprolol exhibits significant β-blocking activity.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Bisoprolol Fumarate
  • Bisoprolol fumerate
  • Bisoprolol Hemifumarate
Brand names
  • Cardicor
  • Concor
  • Condyline
  • Condylox
  • Detensiel
  • Emconcor
  • Emcor
  • Euradal
  • Isoten
  • Monocor (Biovail Pharmaceuticals)
  • Soloc
  • Soprol
  • Zebeta (Barr)
Brand name mixtures
  • Ziac (bisoprolol + hydrochlorothiazide)
Categories
  • Antihypertensive Agents
  • Adrenergic Agents
  • Adrenergic beta-Antagonists
  • Sympatholytics
CAS number 66722-44-9
Weight Average: 325.443
Monoisotopic: 325.225308485
Chemical Formula C18H31NO4
InChI Key InChIKey=VHYCDWMUTMEGQY-UHFFFAOYSA-N
InChI
InChI=1S/C18H31NO4/c1-14(2)19-11-17(20)13-23-18-7-5-16(6-8-18)12-21-9-10-22-15(3)4/h5-8,14-15,17,19-20H,9-13H2,1-4H3
Plain Text
IUPAC Name
[2-hydroxy-3-(4-{[2-(propan-2-yloxy)ethoxy]methyl}phenoxy)propyl](propan-2-yl)amine
SMILES
CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzyl Alcohols and Derivatives
  • Phenols and Derivatives
  • Ethers
  • Anisoles
  • Phenyl Esters
Substructures
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Aliphatic and Aryl Amines
  • Phenols and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Amino Alcohols
  • Aromatic compounds
  • Anisoles
  • Alcohols and Polyols
  • Phenyl Esters
Pharmacology
Indication For management of heart failure, angina pectoris, and mild to moderate hypertension and for secondary prevention of myocardial infarction (MI).
Pharmacodynamics Bisoprolol is a competitive, cardioselective β1-adrenergic antagonist. Activation of β1-receptors (located mainly in the heart) by epinephrine increases heart rate and the blood pressure causing the heart to consume more oxygen. β1-adrenergic blocking agents such as bisopolol lower the heart rate and blood pressure and may be used to reduce workload on the heart and hence oxygen demands. They are routinely prescribed in patients with ischemic heart disease. In addition, β1-selective blockers prevent the release of renin, a hormone produced by the kidneys causes constriction of blood vessels. Bisoprolol is lipophilic and exhibits no intrinsic sympathomimetic activity (ISA) or membrane-stabilizing activity.
Mechanism of action Bisoprolol selectively blocks catecholamine stimulation of β1-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. At higher doses (e.g. 20 mg and greater) bisoprolol may competitively block β2-adrenergic receptors in bronchial and vascular smooth muscle causing bronchospasm and vasodilation.
Absorption Well absorbed. Bioavailability > 80%. Absorption is not affected by food. Peak plasma concentrations occur within 2-4 hours.
Volume of distribution Not Available
Protein binding Binding to serum proteins is approximately 30%
Metabolism

Approximately 50% of the dose is metabolized primarily metabolized by CYP3A4 to inactive metabolites. In vitro studies have shown that bisoprolol is also metabolized by CYP2D6 though this does not appear to be clinically significant. Approximately half the administered dose is excreted in unchanged in urine.

Route of elimination Eliminated equally by renal and non-renal pathways. Approximately 50% of the total orally administered dose is excreted unchanged in urine with the remainder appearing as inactive metabolites. Less than 2% of the dose is excreted in the feces.
Half life 9-12 hours; prolonged in the elderly and those with decreased renal function
Clearance Not Available
Toxicity Oral, mouse: LD50 = 100 mg/kg; Skin, rabbit: LD50 = 200 mg/kg; Skin, rat: LD50 = 500 mg/kg. Symptoms of overdose include congestive heart failure (marked by sudden weight gain, swelling of the legs, feet, and ankles, fatigue, and shortness of breath), difficult or labored breathing, low blood pressure, low blood sugar, and slow heartbeat.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00300 Bisoprolol Pathway SMP00300
Pharmacoeconomics
Manufacturers
  • Aurobindo pharma ltd
  • Mutual pharmaceutical co inc
  • Mylan pharmaceuticals inc
  • Sandoz inc
  • Teva pharmaceuticals usa
  • Unichem pharmaceuticals (usa) inc
  • Duramed pharmaceuticals inc sub barr laboratories inc
Packagers
Dosage forms
Form Route Strength
Tablet, film coated Oral 10 mg
Tablet, film coated Oral 5 mg
Prices
Unit description Cost Unit
Condylox 0.5% Gel 3.5 gm Tube 304.93 USD tube
Condylox 0.5% Solution 3.5ml Bottle 143.4 USD bottle
Condylox 0.5% gel 97.73 USD g
Zebeta 10 mg tablet 3.6 USD tablet
Zebeta 5 mg tablet 3.6 USD tablet
Bisoprolol fumarate 5 mg tablet 1.78 USD tablet
Bisoprolol fumarate 10 mg tablet 1.24 USD tablet
Bisoprolol-Hydrochlorothiazide 10-6.25 mg tablet 1.19 USD tablet
Bisoprolol-Hydrochlorothiazide 2.5-6.25 mg tablet 1.19 USD tablet
Bisoprolol-Hydrochlorothiazide 5-6.25 mg tablet 1.19 USD tablet
Apo-Bisoprolol 10 mg Tablet 0.38 USD tablet
Novo-Bisoprolol 10 mg Tablet 0.38 USD tablet
Pms-Bisoprolol 10 mg Tablet 0.38 USD tablet
Sandoz Bisoprolol 10 mg Tablet 0.38 USD tablet
Apo-Bisoprolol 5 mg Tablet 0.23 USD tablet
Novo-Bisoprolol 5 mg Tablet 0.23 USD tablet
Pms-Bisoprolol 5 mg Tablet 0.23 USD tablet
Sandoz Bisoprolol 5 mg Tablet 0.23 USD tablet
Patents Not Available
Properties
State solid
Melting point 100 oC
Experimental Properties
Property Value Source
water solubility 2240 mg/L PhysProp
logP 2.2 PhysProp
Predicted Properties
Property Value Source
water solubility 7.07e-02 g/l ALOGPS
logP 2.30 ALOGPS
logP 2.20 ChemAxon Molconvert
logS -3.66 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 59.95 ChemAxon Molconvert
rotatable bond count 12 ChemAxon Molconvert
refractivity 92.15 ChemAxon Molconvert
polarizability 38.50 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D02342 Link_out
KEGG Compound C06852 Link_out
PubChem Compound 2405 Link_out
PubChem Substance 46508844 Link_out
ChemSpider 2312 Link_out
BindingDB 25751 Link_out
ChEBI 3127 Link_out
ChEMBL 3127 Link_out
Therapeutic Targets Database DAP000483 Link_out
PharmGKB PA448641 Link_out
Drug Product Database 2247439 Link_out
RxList http://www.rxlist.com/cgi/generic3/bisoprolol.htm Link_out
Drugs.com http://www.drugs.com/bisoprolol.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/zeb1667.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Bisoprolol Link_out
ATC Codes
  • C07AB07
AHFS Codes
  • 24:24.00
PDB Entries Not Available
FDA label Not Available
MSDS show (73.1 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals.
Targets

1. Beta-1 adrenergic receptor

Pharmacological action: yes
Actions: antagonist

Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately equal affinity

Organism class: human
UniProt ID: P08588 Link_out
Gene: ADRB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Breed JG, Ciampricotti R, Tromp GP, Valster FA, Lageweg E, Van Bortel LM: Quality of life perception during antihypertensive treatment: a comparative study of bisoprolol and enalapril. J Cardiovasc Pharmacol. 1992;20(5):750-5. Pubmed
  2. Brouri F, Hanoun N, Mediani O, Saurini F, Hamon M, Vanhoutte PM, Lechat P: Blockade of beta 1- and desensitization of beta 2-adrenoceptors reduce isoprenaline-induced cardiac fibrosis. Eur J Pharmacol. 2004 Feb 6;485(1-3):227-34. Pubmed
  3. Bruck H, Leineweber K, Temme T, Weber M, Heusch G, Philipp T, Brodde OE: The Arg389Gly beta1-adrenoceptor polymorphism and catecholamine effects on plasma-renin activity. J Am Coll Cardiol. 2005 Dec 6;46(11):2111-5. Epub 2005 Nov 4. Pubmed
  4. Lipworth BJ, Irvine NA, McDevitt DG: A dose-ranging study to evaluate the beta 1-adrenoceptor selectivity of bisoprolol. Eur J Clin Pharmacol. 1991;40(2):135-9. Pubmed
  5. Mauz AB, Pelzer H: Beta-adrenoceptor-binding studies of the cardioselective beta blockers bisoprolol, H-I 42 BS, and HX-CH 44 BS to heart membranes and intact ventricular myocytes of adult rats: two beta 1-binding sites for bisoprolol. J Cardiovasc Pharmacol. 1990 Mar;15(3):421-7. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Beta-2 adrenergic receptor

Pharmacological action: no
Actions: antagonist

Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine

Organism class: human
UniProt ID: P07550 Link_out
Gene: ADRB2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Brouri F, Hanoun N, Mediani O, Saurini F, Hamon M, Vanhoutte PM, Lechat P: Blockade of beta 1- and desensitization of beta 2-adrenoceptors reduce isoprenaline-induced cardiac fibrosis. Eur J Pharmacol. 2004 Feb 6;485(1-3):227-34. Pubmed
  2. Bruck H, Poller U, Lussenhop H, Ponicke K, Temme T, Heusch G, Philipp T, Brodde OE: Beta 2-adrenoceptor-mediated intrinsic sympathomimetic activity of carteolol: an in vivo study. Naunyn Schmiedebergs Arch Pharmacol. 2004 Nov;370(5):361-8. Epub 2004 Oct 23. Pubmed
  3. Motomura S, Reinhard-Zerkowski H, Daul A, Brodde OE: On the physiologic role of beta-2 adrenoceptors in the human heart: in vitro and in vivo studies. Am Heart J. 1990 Mar;119(3 Pt 1):608-19. Pubmed
  4. Brodde OE: Bisoprolol (EMD 33512), a highly selective beta 1-adrenoceptor antagonist: in vitro and in vivo studies. J Cardiovasc Pharmacol. 1986;8 Suppl 11:S29-35. Pubmed
  5. Daul A, Johnston T, Reher M, Kruger M, Brodde OE: Differential haemodynamic effects induced by beta 1-(bisoprolol) or beta 2-(ICI 118,551) adrenoceptor blockade in man. J Hypertens Suppl. 1986 Dec;4(6):S99-102. Pubmed
Enzymes

1. Cytochrome P450 3A4

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 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. Horikiri Y, Suzuki T, Mizobe M: Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. J Pharm Sci. 1998 Mar;87(3):289-94. Pubmed
  2. Horikiri Y, Suzuki T, Mizobe M: Stereoselective metabolism of bisoprolol enantiomers in dogs and humans. Life Sci. 1998;63(13):1097-108. 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

2. 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. Horikiri Y, Suzuki T, Mizobe M: Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. J Pharm Sci. 1998 Mar;87(3):289-94. Pubmed
  2. Horikiri Y, Suzuki T, Mizobe M: Stereoselective metabolism of bisoprolol enantiomers in dogs and humans. Life Sci. 1998;63(13):1097-108. Pubmed
  3. Nozawa T, Taguchi M, Tahara K, Hashimoto Y, Igarashi N, Nonomura M, Kato B, Igawa A, Inoue H: Influence of CYP2D6 genotype on metoprolol plasma concentration and beta-adrenergic inhibition during long-term treatment: a comparison with bisoprolol. J Cardiovasc Pharmacol. 2005 Nov;46(5):713-20. Pubmed
  4. 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
Comments
Drug created on June 13, 2005 07:24 / Updated on September 29, 2011 12:48

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.