Welcome to DrugBank 4.0! If you prefer, you can still go back to version 3.0.
Identification
NamePenbutolol
Accession NumberDB01359
Typesmall molecule
Groupsapproved, investigational
Description

Penbutolol is a drug in the beta-blocker class used to treat hypertension. Penbutolol binds both beta-1 and beta-2 adrenergic receptors, rendering it a non-selective beta-blocker. Penbutolol can act as a partial agonist at beta adrenergic receptors, since it is a sympathomimetric drug. Penbutolol also demonstrates high binding affinity to the 5-hydroxytryptamine receptor 1A with antagonistic effects. This binding characteristic of penbutolol is being investigated for its implications in Antidepressant Therapy. Penbutolol is contraindicated in patients with cardiogenic shock, sinus bradycardia, second and third degree atrioventricular conduction block, bronchial asthma, and those with known hypersensitivity.

Structure
Thumb
Synonyms
SynonymLanguageCode
(2S)-1-(tert-butylamino)-3-(2-cyclopentylphenoxy)propan-2-olNot AvailableNot Available
1-(tert-Butylamino)-3-(o-cyclopentylphenoxy)propan-2-olNot AvailableNot Available
2-Propanol, 1-(2-cyclopentylphenoxy)-3-((1,1-dimethylethyl)amino)-, (S)-Not AvailableNot Available
HOE 893Not AvailableNot Available
HOE 893DNot AvailableNot Available
PenbutololumLatinNot Available
Salts
Name/CAS Structure Properties
Penbutolol sulfate
Thumb
  • InChI Key: KTXVDQNRHZQBOR-RSAXXLAASA-N
  • Monoisotopic Mass: 389.187208419
  • Average Mass: 389.507
DBSALT000137
Brand names
NameCompany
BetapressinHoechst Ltd.
LevatolSchwarz Pharma
LevatololNot Available
LobetaSanofi-Aventis
Brand mixturesNot Available
Categories
CAS number36507-48-9
WeightAverage: 291.4284
Monoisotopic: 291.219829177
Chemical FormulaC18H29NO2
InChI KeyInChIKey=KQXKVJAGOJTNJS-HNNXBMFYSA-N
InChI
InChI=1S/C18H29NO2/c1-18(2,3)19-12-15(20)13-21-17-11-7-6-10-16(17)14-8-4-5-9-14/h6-7,10-11,14-15,19-20H,4-5,8-9,12-13H2,1-3H3/t15-/m0/s1
IUPAC Name
tert-butyl[(2S)-3-(2-cyclopentylphenoxy)-2-hydroxypropyl]amine
SMILES
CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1
Mass Specshow(49.2 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenol Ethers
Direct parentPhenol Ethers
Alternative parentsAlkyl Aryl Ethers; Secondary Alcohols; 1,2-Aminoalcohols; Polyamines; Dialkylamines
Substituentsalkyl aryl ether; 1,2-aminoalcohol; secondary alcohol; secondary amine; ether; secondary aliphatic amine; polyamine; amine; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
Pharmacology
IndicationPenbutolol is indicated in the treatment of mild to moderate arterial hypertension. It may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.Penbutolol is contraindicated in patients with cardiogenic shock, sinus bradycardia, second and third degree atrioventricular conduction block, bronchial asthma, and those with known hypersensitivity.
PharmacodynamicsPenbutolol is a ß-1, ß-2 (nonselective) adrenergic receptor antagonist. Experimental studies showed a dose-dependent increase in heart rate in reserpinized (norepinephrine-depleted) rats given penbutolol intravenously at doses of 0.25 to 1.0 mg/kg, suggesting that penbutolol has some intrinsic sympathomimetic activity. In human studies, however, heart rate decreases have been similar to those seen with propranolol.
Mechanism of actionPenbutolol acts on the β1 adrenergic receptors in both the heart and the kidney. When β1 receptors are activated by catecholamines, they stimulate a coupled G protein that leads to the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). The increase in cAMP leads to activation of protein kinase A (PKA), which alters the movement of calcium ions in heart muscle and increases the heart rate. Penbutolol blocks the catecholamine activation of β1 adrenergic receptors and decreases heart rate, which lowers blood pressure.
Absorption>90%.
Volume of distributionNot Available
Protein binding80-98% bound to plasma proteins. Extensively bound to Alpha-1-acid glycoprotein 1.
Metabolism

Metabolized in the liver by hydroxylation and glucuroconjugation forming a glucuronide metabolite and a semi-active 4-hydroxy metabolite.

Route of eliminationThe metabolites are excreted principally in the urine.
Half lifePlasma= approximately 5h Conjugated= approximately 20h in healthy persons, 25h in healthy elderly persons, and 100h in patients on renal dialysis.
Clearance

Approximately 90% of the metabolites are excreted in the urine.

ToxicitySymptoms of overdose include drowsiness, vertigo, headache, and atriventricular block.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Penbutolol Action PathwayDrug actionSMP00305
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9935
Blood Brain Barrier - 0.747
Caco-2 permeable + 0.5961
P-glycoprotein substrate Substrate 0.6827
P-glycoprotein inhibitor I Non-inhibitor 0.7493
P-glycoprotein inhibitor II Non-inhibitor 0.7789
Renal organic cation transporter Non-inhibitor 0.8696
CYP450 2C9 substrate Non-substrate 0.7898
CYP450 2D6 substrate Substrate 0.8919
CYP450 3A4 substrate Non-substrate 0.6339
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Non-inhibitor 0.8899
CYP450 2D6 substrate Inhibitor 0.8932
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7132
Ames test Non AMES toxic 0.8317
Carcinogenicity Non-carcinogens 0.8643
Biodegradation Not ready biodegradable 0.9927
Rat acute toxicity 2.3931 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9436
hERG inhibition (predictor II) Non-inhibitor 0.5704
Pharmacoeconomics
Manufacturers
  • Schwarz pharma inc
Packagers
  • Schwarz Pharma Inc.
Dosage forms
FormRouteStrength
TabletOral20 mg, yellow, oval.
Prices
Unit descriptionCostUnit
Levatol 20 mg tablet2.87USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
boiling point438.2http://www.chemnet.com/cas/fr/38363-40-5/Penbutolol.html
logP4.15HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
water solubility2.12e-02 g/lALOGPS
logP3.84ALOGPS
logP3.55ChemAxon
logS-4.1ALOGPS
pKa (strongest acidic)14.09ChemAxon
pKa (strongest basic)9.76ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count2ChemAxon
polar surface area41.49ChemAxon
rotatable bond count7ChemAxon
refractivity86.6ChemAxon
polarizability34.58ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Maurer HH, Tenberken O, Kratzsch C, Weber AA, Peters FT: Screening for library-assisted identification and fully validated quantification of 22 beta-blockers in blood plasma by liquid chromatography-mass spectrometry with atmospheric pressure chemical ionization. J Chromatogr A. 2004 Nov 26;1058(1-2):169-81. Pubmed
  2. Aguirre C, Rodriguez-Sasiain JM, Calvo R: Decrease in penbutolol protein binding as a consequence of treatment with some alkylating agents. Cancer Chemother Pharmacol. 1994;34(1):86-8. Pubmed
  3. Hjorth S: (-)-Penbutolol as a blocker of central 5-HT1A receptor-mediated responses. Eur J Pharmacol. 1992 Nov 3;222(1):121-7. Pubmed
  4. Pepe S, Scalici G, D’Angelo A, Curiale B, Corrao S, Agnello C: [Validity of the use of penbutolol in essential arterial hypertension]. Minerva Med. 1990 Jun;81(6):471-3. Pubmed
  5. Frishman WH, Covey S: Penbutolol and carteolol: two new beta-adrenergic blockers with partial agonism. J Clin Pharmacol. 1990 May;30(5):412-21. Pubmed
  6. Martinez Jorda R, Aguirre C, Calvo R, Rodriguez-Sasiain JM, Erill S: Decrease in penbutolol central response as a cause of changes in its serum protein binding. J Pharm Pharmacol. 1990 Mar;42(3):164-6. Pubmed
External Links
ResourceLink
KEGG DrugD00602
PubChem Compound37464
PubChem Substance46504929
ChemSpider34369
Therapeutic Targets DatabaseDAP000938
PharmGKBPA164749474
Drugs.comhttp://www.drugs.com/cdi/penbutolol.html
WikipediaPenbutolol
ATC CodesC07AA23
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(56.3 KB)
MSDSshow(568 KB)
Interactions
Drug Interactions
Drug
AminophyllineAntagonism of action and increased effect of theophylline
ChlorpropamideThe beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
ClonidineIncreased hypertension when clonidine stopped
DigoxinBoth digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
DihydroergotamineIschemia with risk of gangrene
DisopyramideThe beta-blocker, penbutolol, may increase the toxicity of disopyramide.
EpinephrineHypertension, then bradycardia
ErgotamineIschemia with risk of gangrene
FenoterolAntagonism
FormoterolAntagonism
GliclazideThe beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
GlyburideThe beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
IbuprofenRisk of inhibition of renal prostaglandins
IndomethacinRisk of inhibition of renal prostaglandins
Insulin GlargineThe beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
LidocainePenbutolol increases the volume of distribution of lidocaine in normal subjects. This could result in a requirement for higher loading doses of lidocaine.
MethyldopaPossible hypertensive crisis
MethysergideIschemia with risk of gangrene
OrciprenalineAntagonism
OxtriphyllineAntagonism of action and increased effect of theophylline
PipobromanAntagonism
PiroxicamRisk of inhibition of renal prostaglandins
PrazosinRisk of hypotension at the beginning of therapy
RepaglinideThe beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
TerazosinIncreased risk of hypotension. Initiate concomitant therapy cautiously.
TerbutalineAntagonism
TheophyllineAntagonism of action and increased effect of theophylline
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food InteractionsNot Available

1. Beta-1 adrenergic receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist partial agonist

Components

Name UniProt ID Details
Beta-1 adrenergic receptor P08588 Details

References:

  1. Venter CP, Joubert PH: Ethnic differences in beta-1-adrenoceptor sensitivity. S Afr Med J. 1982 Nov 27;62(23):849-50. Pubmed
  2. Sanchez C: Effect of serotonergic drugs on footshock-induced ultrasonic vocalization in adult male rats. Behav Pharmacol. 1993 Jun;4(3):269-277. Pubmed
  3. Doze P, Elsinga PH, Maas B, Van Waarde A, Wegman T, Vaalburg W: Synthesis and evaluation of radiolabeled antagonists for imaging of beta-adrenoceptors in the brain with PET. Neurochem Int. 2002 Feb;40(2):145-55. Pubmed
  4. Frishman WH, Covey S: Penbutolol and carteolol: two new beta-adrenergic blockers with partial agonism. J Clin Pharmacol. 1990 May;30(5):412-21. Pubmed

2. Beta-2 adrenergic receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist partial agonist

Components

Name UniProt ID Details
Beta-2 adrenergic receptor P07550 Details

References:

  1. Kulkarni RD, DaSilva LM, Chabria NL, Chadha DR: Beta-2 adrenoceptor blocking activity of penbutolol and propranolol at very low doses. Clin Pharmacol Ther. 1977 Jun;21(6):685-90. Pubmed
  2. Hjorth S, Sharp T: In vivo microdialysis evidence for central serotonin1A and serotonin1B autoreceptor blocking properties of the beta adrenoceptor antagonist (-)penbutolol. J Pharmacol Exp Ther. 1993 May;265(2):707-12. Pubmed
  3. Hjorth S, Bengtsson HJ, Milano S: Raphe 5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or beta-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo. Eur J Pharmacol. 1996 Nov 28;316(1):43-7. Pubmed
  4. Sanchez C: Effect of serotonergic drugs on footshock-induced ultrasonic vocalization in adult male rats. Behav Pharmacol. 1993 Jun;4(3):269-277. Pubmed
  5. Ijzerman AP, Nagesser A, Garritsen A: The membrane stabilizing activity of beta-adrenoceptor ligands. Quantitative evaluation of the interaction of phenoxypropanolamines with the [3H]batrachotoxinin A 20-alpha-benzoate binding site on voltage-sensitive sodium channels in rat brain. Biochem Pharmacol. 1987 Dec 15;36(24):4239-44. Pubmed
  6. Frishman WH, Covey S: Penbutolol and carteolol: two new beta-adrenergic blockers with partial agonism. J Clin Pharmacol. 1990 May;30(5):412-21. Pubmed

3. 5-hydroxytryptamine receptor 1A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 1A P08908 Details

References:

  1. Rabiner EA, Gunn RN, Castro ME, Sargent PA, Cowen PJ, Koepp MJ, Meyer JH, Bench CJ, Harrison PJ, Pazos A, Sharp T, Grasby PM: beta-blocker binding to human 5-HT receptors in vivo and in vitro: implications for antidepressant therapy. Neuropsychopharmacology. 2000 Sep;23(3):285-93. Pubmed
  2. Hjorth S: (-)-Penbutolol as a blocker of central 5-HT1A receptor-mediated responses. Eur J Pharmacol. 1992 Nov 3;222(1):121-7. Pubmed

1. Alpha-1-acid glycoprotein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
Alpha-1-acid glycoprotein 1 P02763 Details

References:

  1. Martinez Jorda R, Aguirre C, Calvo R, Rodriguez-Sasiain JM, Erill S: Decrease in penbutolol central response as a cause of changes in its serum protein binding. J Pharm Pharmacol. 1990 Mar;42(3):164-6. Pubmed
  2. Aguirre C, Rodriguez-Sasiain JM, Calvo R: Decrease in penbutolol protein binding as a consequence of treatment with some alkylating agents. Cancer Chemother Pharmacol. 1994;34(1):86-8. Pubmed
  3. Aguirre C, Calvo R, Rodriguez-Sasiain JM: Unchanged protein binding of penbutolol in renal insufficiency: a possible role of carbamylation. Int J Clin Pharmacol Ther Toxicol. 1993 Jan;31(1):31-4. Pubmed
  4. Aguirre C, Troconiz IF, Valdivieso A, Jimenez RM, Gonzalez JP, Calvo R, Rodriguez-Sasiain JM: Pharmacokinetics and pharmacodynamics of penbutolol in healthy and cancer subjects: role of altered protein binding. Res Commun Mol Pathol Pharmacol. 1996 Apr;92(1):53-72. Pubmed

Comments
Drug created on July 06, 2007 13:52 / Updated on March 14, 2014 14:58