Debrisoquine

Identification

Generic Name
Debrisoquine
DrugBank Accession Number
DB04840
Background

An adrenergic neuron-blocking drug similar in effects to guanethidine. It is also noteworthy in being a substrate for a polymorphic cytochrome P-450 enzyme. Persons with certain isoforms of this enzyme are unable to properly metabolize this and many other clinically important drugs. They are commonly referred to as having a debrisoquin 4-hydroxylase polymorphism.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 175.2303
Monoisotopic: 175.110947431
Chemical Formula
C10H13N3
Synonyms
  • Debrisochinum
  • Debrisoquin
  • Debrisoquina
  • Debrisoquine
  • Débrisoquine
  • Debrisoquinum

Pharmacology

Indication

For the treatment of moderate and severe hypertension, either alone or as an adjunct, and for the treatment of renal hypertension.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Debrisoquin is an adrenergic neuron-blocking drug similar in effects to guanethidine. It is a substrate for a polymorphic cytochrome P-450 enzyme. Persons with certain isoforms of this enzyme are unable to properly metabolize this and many other clinically important drugs. They are commonly referred to as having a debrisoquin 4-hydroxylase polymorphism.

Mechanism of action

Debrisoquin acts at the sympathetic neuroeffector junction by inhibiting or interfering with the release and/or distribution of norepinephrine, rather than acting at the effector cell by inhibiting the association of norepinephrine with its receptors. It is taken up by norepinephrine transporters. It becomes concentrated in NE transmitter vesicles, replacing NE in these vesicles. This leads to a gradual depletion of NE stores in the nerve endings. Once inside the terminal it blocks the release of noradrenaline in response to arrival of an action potential. In contrast to ganglionic blocking agents, debrisoquin suppresses equally the responses mediated by alpha-and beta-adrenergic receptors but does not produce parasympathetic blockade. Since sympathetic blockade results in modest decreases in peripheral resistance and cardiac output, debrisoquin lowers blood pressure in the supine position. It further reduces blood pressure by decreasing the degree of vasoconstriction that normally results from reflex sympathetic nervous activity upon assumption of the upright posture, thus reducing venous return and cardiac output more.

TargetActionsOrganism
ASodium-dependent noradrenaline transporter
inducer
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Hepatic.

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Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbaloparatideAbaloparatide may increase the hypotensive activities of Debrisoquine.
AbataceptThe metabolism of Debrisoquine can be increased when combined with Abatacept.
AbirateroneThe metabolism of Debrisoquine can be decreased when combined with Abiraterone.
AcebutololThe metabolism of Debrisoquine can be decreased when combined with Acebutolol.
AceclofenacThe therapeutic efficacy of Debrisoquine can be decreased when used in combination with Aceclofenac.
Food Interactions
  • Take with or without food. The absorption is unaffected by food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Debrisoquine sulfateQ94064N9NW581-88-4CAYGYVYWRIHZCQ-UHFFFAOYSA-N
International/Other Brands
Bonipress (lkapharm) / Declinax (Roche) / Tendor (Chinoin)

Categories

ATC Codes
C02CC04 — Debrisoquine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as tetrahydroisoquinolines. These are tetrahydrogenated isoquinoline derivatives.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Tetrahydroisoquinolines
Sub Class
Not Available
Direct Parent
Tetrahydroisoquinolines
Alternative Parents
Benzenoids / Guanidines / Carboximidamides / Azacyclic compounds / Organopnictogen compounds / Imines / Hydrocarbon derivatives
Substituents
Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carboximidamide / Guanidine / Hydrocarbon derivative / Imine / Organic nitrogen compound / Organonitrogen compound / Organopnictogen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
carboxamidine, isoquinolines (CHEBI:34665)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
X31CDK040E
CAS number
1131-64-2
InChI Key
JWPGJSVJDAJRLW-UHFFFAOYSA-N
InChI
InChI=1S/C10H13N3/c11-10(12)13-6-5-8-3-1-2-4-9(8)7-13/h1-4H,5-7H2,(H3,11,12)
IUPAC Name
1,2,3,4-tetrahydroisoquinoline-2-carboximidamide
SMILES
NC(=N)N1CCC2=CC=CC=C2C1

References

Synthesis Reference

Wenner,W.; U.S. Patent 3,157,573; November 17,1964; assigned to Hoffmann-LaRoche, Inc.

General References
Not Available
Human Metabolome Database
HMDB0006543
KEGG Compound
C13650
PubChem Compound
2966
PubChem Substance
46507664
ChemSpider
2860
BindingDB
50122613
RxNav
3118
ChEBI
34665
ChEMBL
CHEMBL169901
ZINC
ZINC000003594299
Therapeutic Targets Database
DAP000125
PharmGKB
PA452616
Wikipedia
Debrisoquine

Clinical Trials

Clinical Trials
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableUnknown StatusOtherHealthy Volunteers (HV)1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)278-280 °CPhysProp
logP0.75SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.842 mg/mLALOGPS
logP0.58ALOGPS
logP1.07Chemaxon
logS-2.3ALOGPS
pKa (Strongest Basic)12.47Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area53.11 Å2Chemaxon
Rotatable Bond Count0Chemaxon
Refractivity63.85 m3·mol-1Chemaxon
Polarizability19.48 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9714
Blood Brain Barrier+0.9106
Caco-2 permeable+0.5
P-glycoprotein substrateSubstrate0.8427
P-glycoprotein inhibitor INon-inhibitor0.8781
P-glycoprotein inhibitor IINon-inhibitor0.8382
Renal organic cation transporterInhibitor0.8817
CYP450 2C9 substrateNon-substrate0.8429
CYP450 2D6 substrateSubstrate0.8918
CYP450 3A4 substrateNon-substrate0.7101
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9549
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.9532
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9462
Ames testNon AMES toxic0.7018
CarcinogenicityNon-carcinogens0.976
BiodegradationNot ready biodegradable0.9422
Rat acute toxicity2.7479 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6904
hERG inhibition (predictor II)Inhibitor0.5928
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0ue9-2900000000-5f2dcf1ab6da5e83a08a
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-0900000000-5deb90f73bb93308cff7
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-2900000000-aec4221b654ddee5d07f
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-0900000000-8219978c5f92fed50beb
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00kf-6900000000-198ab5c9c978861573ca
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-0900000000-33463e1195da20620136
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001l-5900000000-11cf232d32ce02e4ccd0
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-141.5480292
predicted
DarkChem Lite v0.1.0
[M-H]-135.38689
predicted
DeepCCS 1.0 (2019)
[M+H]+143.1160292
predicted
DarkChem Lite v0.1.0
[M+H]+138.13324
predicted
DeepCCS 1.0 (2019)
[M+Na]+141.6097292
predicted
DarkChem Lite v0.1.0
[M+Na]+147.29137
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inducer
General Function
Mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline) (PubMed:2008212, PubMed:8125921). Can also mediate sodium- and chloride-dependent transport of dopamine (PubMed:11093780, PubMed:8125921)
Specific Function
actin binding
Gene Name
SLC6A2
Uniprot ID
P23975
Uniprot Name
Sodium-dependent noradrenaline transporter
Molecular Weight
69331.42 Da
References
  1. Joyce PI, Rizzi D, Calo G, Rowbotham DJ, Lambert DG: The effect of guanethidine and local anesthetics on the electrically stimulated mouse vas deferens. Anesth Analg. 2002 Nov;95(5):1339-43, table of contents. [Article]
  2. Bryan-Lluka LJ, Seers H, Sharpe I: Amezinium and debrisoquine are substrates of uptake1 and potent inhibitors of monoamine oxidase in perfused lungs of rats. Naunyn Schmiedebergs Arch Pharmacol. 1996 Apr;353(5):536-44. [Article]
  3. Mitchell JR, Cavanaugh JH, Arias L, Oates JA: Guanethidine and related agents. 3. Antagonism by drugs which inhibit the norepinephrine pump in man. J Clin Invest. 1970 Aug;49(8):1596-604. [Article]
  4. Yi E, Love JA: Alpha-adrenergic modulation of synaptic transmission in rabbit pancreatic ganglia. Auton Neurosci. 2005 Oct 30;122(1-2):45-57. Epub 2005 Aug 25. [Article]
  5. Galli A, Blakely RD, DeFelice LJ: Norepinephrine transporters have channel modes of conduction. Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8671-6. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15041462, PubMed:15805301, PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15041462, PubMed:15805301, PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C15-alpha and C16-alpha positions (PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15805301). Displays different regioselectivities for polyunsaturated fatty acids (PUFA) hydroxylation (PubMed:15041462, PubMed:18577768). Catalyzes the epoxidation of double bonds of certain PUFA (PubMed:15041462, PubMed:19965576, PubMed:20972997). Converts arachidonic acid toward epoxyeicosatrienoic acid (EET) regioisomers, 8,9-, 11,12-, and 14,15-EET, that function as lipid mediators in the vascular system (PubMed:20972997). Displays an absolute stereoselectivity in the epoxidation of eicosapentaenoic acid (EPA) producing the 17(R),18(S) enantiomer (PubMed:15041462). May play an important role in all-trans retinoic acid biosynthesis in extrahepatic tissues. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195)
Specific Function
arachidonic acid monooxygenase activity
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Granvil CP, Krausz KW, Gelboin HV, Idle JR, Gonzalez FJ: 4-Hydroxylation of debrisoquine by human CYP1A1 and its inhibition by quinidine and quinine. J Pharmacol Exp Ther. 2002 Jun;301(3):1025-32. doi: 10.1124/jpet.301.3.1025. [Article]
Details
2. Cytochrome P450 2D6
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
Specific Function
anandamide 11,12 epoxidase activity
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Flockhart Table of Drug Interactions [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function
ABC-type xenobiotic transporter activity
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
ATP-dependent translocase ABCB1
Molecular Weight
141477.255 Da
References
  1. 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. [Article]

Drug created at September 26, 2007 15:28 / Updated at August 02, 2024 07:35