Identification

Name
Penbutolol
Accession Number
DB01359
Type
Small Molecule
Groups
Approved, 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
  • (2S)-1-(tert-butylamino)-3-(2-cyclopentylphenoxy)propan-2-ol
  • 1-(tert-Butylamino)-3-(o-cyclopentylphenoxy)propan-2-ol
  • 2-Propanol, 1-(2-cyclopentylphenoxy)-3-((1,1-dimethylethyl)amino)-, (S)-
  • HOE 893
  • HOE 893D
  • Penbutolol
  • Penbutololum
Product Ingredients
IngredientUNIICASInChI Key
Penbutolol sulfateUS7143322838363-32-5KTXVDQNRHZQBOR-RSAXXLAASA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LevatolTablet20 mg/1OralActient Pharmaceuticals, LLC2012-01-252014-06-18Us
LevatolTablet20 mg/1OralUcb Inc1995-06-152013-01-27Us
International/Other Brands
Betapressin (Hoechst Ltd.) / Levatol / Levatolol / Lobeta (Sanofi-Aventis)
Categories
UNII
78W62V43DY
CAS number
38363-40-5
Weight
Average: 291.4284
Monoisotopic: 291.219829177
Chemical Formula
C18H29NO2
InChI Key
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
(2S)-1-(tert-butylamino)-3-(2-cyclopentylphenoxy)propan-2-ol
SMILES
CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1

Pharmacology

Indication

Penbutolol 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.

Pharmacodynamics

Penbutolol 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 action

Penbutolol 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.

TargetActionsOrganism
ABeta-1 adrenergic receptor
antagonist
partial agonist
Human
ABeta-2 adrenergic receptor
antagonist
partial agonist
Human
A5-hydroxytryptamine receptor 1A
antagonist
Human
U5-hydroxytryptamine receptor 1B
antagonist
Human
Absorption

>90%.

Volume of distribution
Not Available
Protein binding

80-98% 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 elimination

The metabolites are excreted principally in the urine.

Half life

Plasma= 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.

Toxicity

Symptoms of overdose include drowsiness, vertigo, headache, and atriventricular block.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Penbutolol Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of adverse effects can be increased when Penbutolol is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of adverse effects can be increased when Penbutolol is combined with (S)-Warfarin.
1,10-Phenanthroline1,10-Phenanthroline may increase the bradycardic activities of Penbutolol.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Penbutolol is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineThe risk or severity of adverse effects can be increased when Penbutolol is combined with 3-isobutyl-1-methyl-7H-xanthine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when Penbutolol is combined with 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Penbutolol is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarinThe risk or severity of adverse effects can be increased when Penbutolol is combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe therapeutic efficacy of 4-Methoxyamphetamine can be decreased when used in combination with Penbutolol.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Penbutolol is combined with 5-methoxy-N,N-dimethyltryptamine.
Food Interactions
Not Available

References

General References
  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:15595665]
  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:8174208]
  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:1468487]
  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:2359502]
  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:2189902]
  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:1974610]
External Links
Human Metabolome Database
HMDB0015447
KEGG Drug
D00602
KEGG Compound
C07416
PubChem Compound
37464
PubChem Substance
46504929
ChemSpider
34369
ChEBI
7954
ChEMBL
CHEMBL1290
Therapeutic Targets Database
DAP000938
PharmGKB
PA164749474
Drugs.com
Drugs.com Drug Page
Wikipedia
Penbutolol
ATC Codes
C07CA23 — Penbutolol and other diureticsC07AA23 — Penbutolol
FDA label
Download (56.3 KB)
MSDS
Download (568 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Schwarz Pharma Inc.
Dosage forms
FormRouteStrength
TabletOral20 mg/1
Prices
Unit descriptionCostUnit
Levatol 20 mg tablet2.87USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)438.2http://www.chemnet.com/cas/fr/38363-40-5/Penbutolol.html
logP4.15HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.0212 mg/mLALOGPS
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 Area41.49 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity86.6 m3·mol-1ChemAxon
Polarizability34.58 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9935
Blood Brain Barrier-0.747
Caco-2 permeable+0.5961
P-glycoprotein substrateSubstrate0.6827
P-glycoprotein inhibitor INon-inhibitor0.7493
P-glycoprotein inhibitor IINon-inhibitor0.7789
Renal organic cation transporterNon-inhibitor0.8696
CYP450 2C9 substrateNon-substrate0.7898
CYP450 2D6 substrateSubstrate0.8919
CYP450 3A4 substrateNon-substrate0.6339
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.8899
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7132
Ames testNon AMES toxic0.8317
CarcinogenicityNon-carcinogens0.8643
BiodegradationNot ready biodegradable0.9927
Rat acute toxicity2.3931 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9436
hERG inhibition (predictor II)Non-inhibitor0.5704
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (49.2 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenol ethers
Sub Class
Not Available
Direct Parent
Phenol ethers
Alternative Parents
Phenoxy compounds / Alkyl aryl ethers / Secondary alcohols / 1,2-aminoalcohols / Dialkylamines / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Phenoxy compound / Phenol ether / Alkyl aryl ether / Monocyclic benzene moiety / 1,2-aminoalcohol / Secondary alcohol / Secondary aliphatic amine / Secondary amine / Ether / Organic nitrogen compound
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
ethanolamines (CHEBI:7954)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
Partial agonist
General Function
Receptor signaling protein activity
Specific Function
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 e...
Gene Name
ADRB1
Uniprot ID
P08588
Uniprot Name
Beta-1 adrenergic receptor
Molecular Weight
51322.1 Da
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:6755764]
  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:11224195]
  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:11738481]
  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:2189902]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
Partial agonist
General Function
Protein homodimerization activity
Specific Function
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 ...
Gene Name
ADRB2
Uniprot ID
P07550
Uniprot Name
Beta-2 adrenergic receptor
Molecular Weight
46458.32 Da
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:16716]
  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:8098761]
  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:8982649]
  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:11224195]
  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:2446632]
  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:2189902]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...
Gene Name
HTR1A
Uniprot ID
P08908
Uniprot Name
5-hydroxytryptamine receptor 1A
Molecular Weight
46106.335 Da
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(1A) receptors in vivo and in vitro: implications for antidepressant therapy. Neuropsychopharmacology. 2000 Sep;23(3):285-93. [PubMed:10942852]
  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:1468487]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive subst...
Gene Name
HTR1B
Uniprot ID
P28222
Uniprot Name
5-hydroxytryptamine receptor 1B
Molecular Weight
43567.535 Da
References
  1. 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:8098761]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Iwaki M, Niwa T, Bandoh S, Itoh M, Hirose H, Kawase A, Komura H: Application of substrate depletion assay to evaluation of CYP isoforms responsible for stereoselective metabolism of carvedilol. Drug Metab Pharmacokinet. 2016 Dec;31(6):425-432. doi: 10.1016/j.dmpk.2016.08.007. Epub 2016 Sep 2. [PubMed:27836712]
  2. Brodde OE, Kroemer HK: Drug-drug interactions of beta-adrenoceptor blockers. Arzneimittelforschung. 2003;53(12):814-22. [PubMed:14732961]
  3. Sternieri E, Coccia CP, Pinetti D, Guerzoni S, Ferrari A: Pharmacokinetics and interactions of headache medications, part II: prophylactic treatments. Expert Opin Drug Metab Toxicol. 2006 Dec;2(6):981-1007. doi: 10.1517/17425255.2.6.981 . [PubMed:17125412]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Other/unknown
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
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:1974610]
  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:8174208]
  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:8444514]
  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:8733828]

Drug created on July 06, 2007 13:52 / Updated on November 02, 2018 08:32