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Identification
NameBisoprolol
Accession NumberDB00612  (APRD00257)
Typesmall molecule
Groupsapproved
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
Synonyms
SynonymLanguageCode
(+-)-1-((alpha-(2-Isopropoxyethoxy)-P-tolyl)oxy)-3-(isopropylamino)-2-propanolNot AvailableNot Available
(RS)-1-(4-(2-isopropoxyethoxymethyl)phenoxy)-3-(isopropylamino)-2-propanolNot AvailableNot Available
BisoprololFrench/German/SpanishINN
BisoprololumLatinINN
Salts
Name/CAS Structure Properties
Bisoprolol Fumarate
Thumb Not applicable DBSALT001015
Brand names
NameCompany
CardicorBayer
ConcorMerck
ConcoreMerck
DetensielMerck Santé
EmconcorMerck
EmcorMerck
EuradalLacer
IsotenMeda
MonocorBiovail Pharmaceuticals
SoprolHelsinn
ZebetaBarr
Brand mixtures
Brand NameIngredients
Concor plus bisoprolol + hydrochlorothiazide
Emcoreticbisoprolol + hydrochlorothiazide
Lodozbisoprolol + hydrochlorothiazide
Maxsotenbisoprolol + hydrochlorothiazide
Tebisbisoprolol + hydrochlorothiazide
Wytensbisoprolol + hydrochlorothiazide
Zabesta-XLObisoprolol + hydrochlorothiazide
Ziacbisoprolol + hydrochlorothiazide
Categories
CAS number66722-44-9
WeightAverage: 325.443
Monoisotopic: 325.225308485
Chemical FormulaC18H31NO4
InChI KeyVHYCDWMUTMEGQY-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
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassBenzylethers
Direct parentBenzylethers
Alternative parentsPhenol Ethers; Alkyl Aryl Ethers; Secondary Alcohols; 1,2-Aminoalcohols; Dialkyl Ethers; Polyamines; Dialkylamines
Substituentsphenol ether; alkyl aryl ether; 1,2-aminoalcohol; secondary alcohol; secondary aliphatic amine; dialkyl ether; secondary amine; ether; polyamine; amine; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the benzylethers. These are aromatic ethers with the general formula ROCR' (R = alkyl, aryl; R'=benzene).
Pharmacology
IndicationFor management of heart failure, angina pectoris, and mild to moderate hypertension and for secondary prevention of myocardial infarction (MI).
PharmacodynamicsBisoprolol 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 actionBisoprolol 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.
AbsorptionWell absorbed. Bioavailability > 80%. Absorption is not affected by food. Peak plasma concentrations occur within 2-4 hours.
Volume of distributionNot Available
Protein bindingBinding 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 eliminationEliminated 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 life9-12 hours; prolonged in the elderly and those with decreased renal function
ClearanceNot Available
ToxicityOral, 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
PathwayCategorySMPDB ID
Bisoprolol Action PathwayDrug actionSMP00300
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9445
Blood Brain Barrier - 0.9077
Caco-2 permeable + 0.6149
P-glycoprotein substrate Substrate 0.7785
P-glycoprotein inhibitor I Non-inhibitor 0.807
P-glycoprotein inhibitor II Non-inhibitor 0.7821
Renal organic cation transporter Non-inhibitor 0.8568
CYP450 2C9 substrate Non-substrate 0.8134
CYP450 2D6 substrate Substrate 0.8919
CYP450 3A4 substrate Non-substrate 0.6113
CYP450 1A2 substrate Non-inhibitor 0.9046
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.923
CYP450 2C19 substrate Non-inhibitor 0.9485
CYP450 3A4 substrate Non-inhibitor 0.8373
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9766
Ames test Non AMES toxic 0.9064
Carcinogenicity Non-carcinogens 0.9267
Biodegradation Not ready biodegradable 0.8962
Rat acute toxicity 2.0089 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7877
hERG inhibition (predictor II) Non-inhibitor 0.6611
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
FormRouteStrength
Tablet, film coatedOral10 mg
Tablet, film coatedOral5 mg
Prices
Unit descriptionCostUnit
Condylox 0.5% Gel 3.5 gm Tube304.93USDtube
Condylox 0.5% Solution 3.5ml Bottle143.4USDbottle
Condylox 0.5% gel97.73USDg
Zebeta 10 mg tablet3.6USDtablet
Zebeta 5 mg tablet3.6USDtablet
Bisoprolol fumarate 5 mg tablet1.78USDtablet
Bisoprolol fumarate 10 mg tablet1.24USDtablet
Bisoprolol-Hydrochlorothiazide 10-6.25 mg tablet1.19USDtablet
Bisoprolol-Hydrochlorothiazide 2.5-6.25 mg tablet1.19USDtablet
Bisoprolol-Hydrochlorothiazide 5-6.25 mg tablet1.19USDtablet
Apo-Bisoprolol 10 mg Tablet0.38USDtablet
Novo-Bisoprolol 10 mg Tablet0.38USDtablet
Pms-Bisoprolol 10 mg Tablet0.38USDtablet
Sandoz Bisoprolol 10 mg Tablet0.38USDtablet
Apo-Bisoprolol 5 mg Tablet0.23USDtablet
Novo-Bisoprolol 5 mg Tablet0.23USDtablet
Pms-Bisoprolol 5 mg Tablet0.23USDtablet
Sandoz Bisoprolol 5 mg Tablet0.23USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point100 °CPhysProp
water solubility2240 mg/LNot Available
logP1.87RECANATINI,M (1992)
Predicted Properties
PropertyValueSource
water solubility7.07e-02 g/lALOGPS
logP2.3ALOGPS
logP2.2ChemAxon
logS-3.7ALOGPS
pKa (strongest acidic)14.09ChemAxon
pKa (strongest basic)9.67ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count2ChemAxon
polar surface area59.95ChemAxon
rotatable bond count12ChemAxon
refractivity92.15ChemAxon
polarizability38.5ChemAxon
number of rings1ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Yoshihiro Iwao, Katsuyuki Ookubo, Katsuhiro Okada, Kunihiro Minami, Shuichiro Yuasa, “Adhesive Pharmaceutical Preparation Containing Bisoprolol.” U.S. Patent US20090169604, issued July 02, 2009.

US20090169604
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD02342
KEGG CompoundC06852
PubChem Compound2405
PubChem Substance46508844
ChemSpider2312
BindingDB25751
ChEBI3127
ChEMBLCHEMBL645
Therapeutic Targets DatabaseDAP000483
PharmGKBPA448641
Drug Product Database2247439
RxListhttp://www.rxlist.com/cgi/generic3/bisoprolol.htm
Drugs.comhttp://www.drugs.com/bisoprolol.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/zeb1667.shtml
WikipediaBisoprolol
ATC CodesC07AB07
AHFS Codes
  • 24:24.00
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(73.1 KB)
Interactions
Drug Interactions
Drug
AcetohexamideThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
ChlorpropamideThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
ClonidineIncreased hypertension when clonidine stopped
DihydroergotamineIschemia with risk of gangrene
DisopyramideThe beta-blocker, bisoprolol, may increase the toxicity of disopyramide.
EpinephrineHypertension, then bradycardia
ErgonovineIschemia with risk of gangrene
ErgotamineIschemia with risk of gangrene
FenoterolAntagonism
FormoterolAntagonism
GliclazideThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
GlipizideThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
GlisoxepideThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
GlyburideThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
GlycodiazineThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
IbuprofenRisk of inhibition of renal prostaglandins
IndacaterolBeta-adrenergic antagonists, especially those that are not cardioselective, may interfere with the effect of indacaterol when administered concurrently. Beta-blockers may exacerbate bronchospasms in patients with COPD.
IndomethacinRisk of inhibition of renal prostaglandins
Insulin AspartThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
Insulin DetemirThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
Insulin GlargineThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
Insulin GlulisineThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
Insulin LisproThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
IsoprenalineAntagonism
LidocaineThe beta-blocker, bisoprolol, may increase the effect and toxicity of lidocaine.
MethysergideIschemia with risk of gangrene
OrciprenalineAntagonism
PipobromanAntagonism
PirbuterolAntagonism
PiroxicamRisk of inhibition of renal prostaglandins
PrazosinRisk of hypotension at the beginning of therapy
ProcaterolAntagonism
RepaglinideThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
RifampicinRifampin may decrease the serum concentration of bisprolol by increasing its metabolism.
SalbutamolAntagonism
SalmeterolAntagonism
TelithromycinTelithromycin may reduce clearance of Bisoprolol. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Bisoprolol if Telithromycin is initiated, discontinued or dose changed.
TerazosinIncreased risk of hypotension. Initiate concomitant therapy cautiously.
TerbutalineAntagonism
TolazamideThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
TolbutamideThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
VerapamilIncreased effect of both drugs
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of bisoprolol by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bisoprolol if voriconazole is initiated, discontinued or dose changed.
Food Interactions
  • Take without regard to meals.

Targets

1. Beta-1 adrenergic receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Beta-1 adrenergic receptor P08588 Details

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

Kind: protein

Organism: Human

Pharmacological action: no

Actions: antagonist

Components

Name UniProt ID Details
Beta-2 adrenergic receptor P07550 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11