Identification

Name
Mibefradil
Accession Number
DB01388
Type
Small Molecule
Groups
Investigational, Withdrawn
Description

Mibefradil was withdrawn from the market in 1998 because of potentially harmful interactions with other drugs.

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Posicor
Categories
UNII
27B90X776A
CAS number
116644-53-2
Weight
Average: 495.6287
Monoisotopic: 495.289720302
Chemical Formula
C29H38FN3O3
InChI Key
HBNPJJILLOYFJU-VMPREFPWSA-N
InChI
InChI=1S/C29H38FN3O3/c1-20(2)28-23-12-11-22(30)18-21(23)13-14-29(28,36-27(34)19-35-4)15-17-33(3)16-7-10-26-31-24-8-5-6-9-25(24)32-26/h5-6,8-9,11-12,18,20,28H,7,10,13-17,19H2,1-4H3,(H,31,32)/t28-,29-/m0/s1
IUPAC Name
(1S,2S)-2-(2-{[3-(1H-1,3-benzodiazol-2-yl)propyl](methyl)amino}ethyl)-6-fluoro-1-(propan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl 2-methoxyacetate
SMILES
COCC(=O)O[C@]1(CCN(C)CCCC2=NC3=CC=CC=C3N2)CCC2=C(C=CC(F)=C2)[C@@H]1C(C)C

Pharmacology

Indication

For the treatment of angina and high blood pressure.

Pharmacodynamics

Mibefradil belongs to a group of medicines called calcium channel blocking agents, or, more commonly, calcium channel blockers. Calcium channel blocking agents affect the movement of calcium into the cells of the heart and blood vessels. As a result, they relax blood vessels and increase the supply of blood and oxygen to the heart while reducing its workload. Mibefradil is a benzimidazoyl-substituted tetraline that selectively binds and inhibits T-type calcium channels.

Mechanism of action

Mibefradil is a tetralol calcium channel blocking agent that inhibits the influx of calcium ions across both the T (low-voltage) and L (high-voltage) calcium channels of cardiac and vascular smooth muscle, with a greater selectivity for T channels. Vasodilation occurs in vascular smooth muscle, causing a decrease in peripheral vascular resistance and a resulting decrease in blood pressure. Mibefradil causes a slight increase in cardiac output during chronic dosing. Mibefradil slows sinus and atrioventricular (AV) node conduction, producing a slight reduction in heart rate and a slight increase in the PR interval. It has also been shown to slightly lengthen the corrected sinus node recovery time and AH interval and to raise the Wenckebach point. The mechanism by which mibefradil reduces angina is not known, but is thought to be attributed to a reduction in heart rate, total peripheral resistance (afterload), and the heart rate–systolic blood pressure product at any given level of exercise. The result of these effects is a decrease in cardiac workload and myocardial oxygen demand.

TargetActionsOrganism
AVoltage-dependent T-type calcium channel subunit alpha-1G
inhibitor
Human
AVoltage-dependent T-type calcium channel subunit alpha-1H
inhibitor
Human
AVoltage-dependent L-type calcium channel subunit alpha-1C
inhibitor
Human
AVoltage-dependent L-type calcium channel subunit alpha-1D
inhibitor
Human
AVoltage-dependent L-type calcium channel subunit alpha-1F
inhibitor
Human
AVoltage-dependent T-type calcium channel subunit alpha-1I
inhibitor
Human
AVoltage-dependent L-type calcium channel subunit alpha-1S
inhibitor
Human
AVoltage-dependent L-type calcium channel subunit beta-1
inhibitor
Human
AVoltage-dependent L-type calcium channel subunit beta-2
inhibitor
Human
AVoltage-dependent L-type calcium channel subunit beta-3
inhibitor
Human
AVoltage-dependent L-type calcium channel subunit beta-4
inhibitor
Human
Absorption

Bioavailability after a single dose is 70%. After multiple dosing, the proportion of mibefradil undergoing first-pass metabolism is reduced, resulting in a steady state bioavailability of approximately 90%. Food does not affect the rate or extent of absorption of mibefradil.

Volume of distribution
Not Available
Protein binding

≥ 99%, primarily to alpha 1-acid glycoprotein.

Metabolism

The two metabolic pathways that mibefradil undergoes are esterase-catalyzed hydrolysis of the ester side chain (producing an alcohol metabolite) and cytochrome P450 3A4-catalyzed oxidation (that becomes less important during chronic dosing). The pharmacologic effect of the metabolite is approximately 10% of that of the parent mibefradil.

Route of elimination
Not Available
Half life

17 to 25 hours at steady state.

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Mibefradil.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Mibefradil.
16-BromoepiandrosteroneThe metabolism of 16-Bromoepiandrosterone can be decreased when combined with Mibefradil.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Mibefradil.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Mibefradil.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Mibefradil.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Mibefradil.
AbafunginThe therapeutic efficacy of Abafungin can be increased when used in combination with Mibefradil.
AbemaciclibThe risk or severity of adverse effects can be increased when Mibefradil is combined with Abemaciclib.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Mibefradil.
Food Interactions
Not Available

References

General References
Not Available
External Links
KEGG Compound
C07222
PubChem Compound
60663
PubChem Substance
46504498
ChemSpider
54673
BindingDB
50117922
ChEBI
6920
ChEMBL
CHEMBL45816
Therapeutic Targets Database
DCL000341
PharmGKB
PA450492
Wikipedia
Mibefradil
ATC Codes
C08CX01 — Mibefradil

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentBrain and Central Nervous System Tumors1
1CompletedTreatmentGlioblastoma Multiforme (GBM)1
1CompletedTreatmentHealthy Volunteers / No Condition. Assessment of Healthy Volunteers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
Caco2 permeability-4.87ADME Research, USCD
Predicted Properties
PropertyValueSource
Water Solubility0.00104 mg/mLALOGPS
logP5.34ALOGPS
logP5.16ChemAxon
logS-5.7ALOGPS
pKa (Strongest Acidic)12.54ChemAxon
pKa (Strongest Basic)9.82ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area67.45 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity139.73 m3·mol-1ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9964
Blood Brain Barrier+0.5
Caco-2 permeable+0.5
P-glycoprotein substrateSubstrate0.9087
P-glycoprotein inhibitor IInhibitor0.8718
P-glycoprotein inhibitor IIInhibitor0.8388
Renal organic cation transporterNon-inhibitor0.549
CYP450 2C9 substrateNon-substrate0.8596
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.7408
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorInhibitor0.796
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6921
Ames testNon AMES toxic0.6864
CarcinogenicityNon-carcinogens0.892
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.8610 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9611
hERG inhibition (predictor II)Inhibitor0.7742
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 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 tetralins. These are polycyclic aromatic compounds containing a tetralin moiety, which consists of a benzene fused to a cyclohexane.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Tetralins
Sub Class
Not Available
Direct Parent
Tetralins
Alternative Parents
Benzimidazoles / Aralkylamines / Aryl fluorides / Heteroaromatic compounds / Imidazoles / Trialkylamines / Amino acids and derivatives / Carboxylic acid esters / Dialkyl ethers / Azacyclic compounds
show 6 more
Substituents
Tetralin / Benzimidazole / Aralkylamine / Aryl fluoride / Aryl halide / Imidazole / Azole / Heteroaromatic compound / Amino acid or derivatives / Carboxylic acid ester
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tetralins (CHEBI:6920)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Scaffold protein binding
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1G
Uniprot ID
O43497
Uniprot Name
Voltage-dependent T-type calcium channel subunit alpha-1G
Molecular Weight
262468.62 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20. Epub 2006 Aug 7. [PubMed:16899990]
  3. Monteil A, Chemin J, Bourinet E, Mennessier G, Lory P, Nargeot J: Molecular and functional properties of the human alpha(1G) subunit that forms T-type calcium channels. J Biol Chem. 2000 Mar 3;275(9):6090-100. [PubMed:10692398]
  4. Massie BM: Mibefradil: a selective T-type calcium antagonist. Am J Cardiol. 1997 Nov 6;80(9A):23I-32I. [PubMed:9375939]
  5. Clozel JP, Ertel EA, Ertel SI: Discovery and main pharmacological properties of mibefradil (Ro 40-5967), the first selective T-type calcium channel blocker. J Hypertens Suppl. 1997 Dec;15(5):S17-25. [PubMed:9481612]
  6. McNulty MM, Hanck DA: State-dependent mibefradil block of Na+ channels. Mol Pharmacol. 2004 Dec;66(6):1652-61. [PubMed:15562257]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Scaffold protein binding
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1H
Uniprot ID
O95180
Uniprot Name
Voltage-dependent T-type calcium channel subunit alpha-1H
Molecular Weight
259160.2 Da
References
  1. Brueggemann LI, Martin BL, Barakat J, Byron KL, Cribbs LL: Low voltage-activated calcium channels in vascular smooth muscle: T-type channels and AVP-stimulated calcium spiking. Am J Physiol Heart Circ Physiol. 2005 Feb;288(2):H923-35. Epub 2004 Oct 21. [PubMed:15498818]
  2. Coste B, Crest M, Delmas P: Pharmacological dissection and distribution of NaN/Nav1.9, T-type Ca2+ currents, and mechanically activated cation currents in different populations of DRG neurons. J Gen Physiol. 2007 Jan;129(1):57-77. [PubMed:17190903]
  3. Cribbs LL, Lee JH, Yang J, Satin J, Zhang Y, Daud A, Barclay J, Williamson MP, Fox M, Rees M, Perez-Reyes E: Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family. Circ Res. 1998 Jul 13;83(1):103-9. [PubMed:9670923]
  4. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20. Epub 2006 Aug 7. [PubMed:16899990]
  5. Perez-Reyes E: Paradoxical role of T-type calcium channels in coronary smooth muscle. Mol Interv. 2004 Feb;4(1):16-8. [PubMed:14993472]
  6. Massie BM: Mibefradil: a selective T-type calcium antagonist. Am J Cardiol. 1997 Nov 6;80(9A):23I-32I. [PubMed:9375939]
  7. Clozel JP, Ertel EA, Ertel SI: Discovery and main pharmacological properties of mibefradil (Ro 40-5967), the first selective T-type calcium channel blocker. J Hypertens Suppl. 1997 Dec;15(5):S17-25. [PubMed:9481612]
  8. McNulty MM, Hanck DA: State-dependent mibefradil block of Na+ channels. Mol Pharmacol. 2004 Dec;66(6):1652-61. [PubMed:15562257]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1C
Uniprot ID
Q13936
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1C
Molecular Weight
248974.1 Da
References
  1. Moosmang S, Haider N, Bruderl B, Welling A, Hofmann F: Antihypertensive effects of the putative T-type calcium channel antagonist mibefradil are mediated by the L-type calcium channel Cav1.2. Circ Res. 2006 Jan 6;98(1):105-10. Epub 2005 Nov 23. [PubMed:16306443]
  2. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20. Epub 2006 Aug 7. [PubMed:16899990]
  3. Mocanu MM, Gadgil S, Yellon DM, Baxter GF: Mibefradil, a T-type and L-type calcium channel blocker, limits infarct size through a glibenclamide-sensitive mechanism. Cardiovasc Drugs Ther. 1999 Apr;13(2):115-22. [PubMed:10372226]
  4. Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, Nargeot J: Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology. 2000;39(1):1-10. [PubMed:10665814]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity involved sa node cell action potential
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1D
Uniprot ID
Q01668
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1D
Molecular Weight
245138.75 Da
References
  1. Mocanu MM, Gadgil S, Yellon DM, Baxter GF: Mibefradil, a T-type and L-type calcium channel blocker, limits infarct size through a glibenclamide-sensitive mechanism. Cardiovasc Drugs Ther. 1999 Apr;13(2):115-22. [PubMed:10372226]
  2. Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, Nargeot J: Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology. 2000;39(1):1-10. [PubMed:10665814]
  3. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20. Epub 2006 Aug 7. [PubMed:16899990]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1F
Uniprot ID
O60840
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1F
Molecular Weight
220675.9 Da
References
  1. Mocanu MM, Gadgil S, Yellon DM, Baxter GF: Mibefradil, a T-type and L-type calcium channel blocker, limits infarct size through a glibenclamide-sensitive mechanism. Cardiovasc Drugs Ther. 1999 Apr;13(2):115-22. [PubMed:10372226]
  2. Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, Nargeot J: Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology. 2000;39(1):1-10. [PubMed:10665814]
  3. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20. Epub 2006 Aug 7. [PubMed:16899990]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1I
Uniprot ID
Q9P0X4
Uniprot Name
Voltage-dependent T-type calcium channel subunit alpha-1I
Molecular Weight
245100.8 Da
References
  1. Massie BM: Mibefradil: a selective T-type calcium antagonist. Am J Cardiol. 1997 Nov 6;80(9A):23I-32I. [PubMed:9375939]
  2. Clozel JP, Ertel EA, Ertel SI: Discovery and main pharmacological properties of mibefradil (Ro 40-5967), the first selective T-type calcium channel blocker. J Hypertens Suppl. 1997 Dec;15(5):S17-25. [PubMed:9481612]
  3. McNulty MM, Hanck DA: State-dependent mibefradil block of Na+ channels. Mol Pharmacol. 2004 Dec;66(6):1652-61. [PubMed:15562257]
  4. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20. Epub 2006 Aug 7. [PubMed:16899990]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1S
Uniprot ID
Q13698
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1S
Molecular Weight
212348.1 Da
References
  1. Mocanu MM, Gadgil S, Yellon DM, Baxter GF: Mibefradil, a T-type and L-type calcium channel blocker, limits infarct size through a glibenclamide-sensitive mechanism. Cardiovasc Drugs Ther. 1999 Apr;13(2):115-22. [PubMed:10372226]
  2. Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, Nargeot J: Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology. 2000;39(1):1-10. [PubMed:10665814]
  3. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20. Epub 2006 Aug 7. [PubMed:16899990]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and ina...
Gene Name
CACNB1
Uniprot ID
Q02641
Uniprot Name
Voltage-dependent L-type calcium channel subunit beta-1
Molecular Weight
65712.995 Da
References
  1. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20. Epub 2006 Aug 7. [PubMed:16899990]
  2. Mocanu MM, Gadgil S, Yellon DM, Baxter GF: Mibefradil, a T-type and L-type calcium channel blocker, limits infarct size through a glibenclamide-sensitive mechanism. Cardiovasc Drugs Ther. 1999 Apr;13(2):115-22. [PubMed:10372226]
  3. Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, Nargeot J: Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology. 2000;39(1):1-10. [PubMed:10665814]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and ina...
Gene Name
CACNB2
Uniprot ID
Q08289
Uniprot Name
Voltage-dependent L-type calcium channel subunit beta-2
Molecular Weight
73579.925 Da
References
  1. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20. Epub 2006 Aug 7. [PubMed:16899990]
  2. Mocanu MM, Gadgil S, Yellon DM, Baxter GF: Mibefradil, a T-type and L-type calcium channel blocker, limits infarct size through a glibenclamide-sensitive mechanism. Cardiovasc Drugs Ther. 1999 Apr;13(2):115-22. [PubMed:10372226]
  3. Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, Nargeot J: Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology. 2000;39(1):1-10. [PubMed:10665814]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and ina...
Gene Name
CACNB3
Uniprot ID
P54284
Uniprot Name
Voltage-dependent L-type calcium channel subunit beta-3
Molecular Weight
54531.425 Da
References
  1. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20. Epub 2006 Aug 7. [PubMed:16899990]
  2. Mocanu MM, Gadgil S, Yellon DM, Baxter GF: Mibefradil, a T-type and L-type calcium channel blocker, limits infarct size through a glibenclamide-sensitive mechanism. Cardiovasc Drugs Ther. 1999 Apr;13(2):115-22. [PubMed:10372226]
  3. Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, Nargeot J: Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology. 2000;39(1):1-10. [PubMed:10665814]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and ina...
Gene Name
CACNB4
Uniprot ID
O00305
Uniprot Name
Voltage-dependent L-type calcium channel subunit beta-4
Molecular Weight
58168.625 Da
References
  1. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology. 2006;78(1):11-20. Epub 2006 Aug 7. [PubMed:16899990]
  2. Mocanu MM, Gadgil S, Yellon DM, Baxter GF: Mibefradil, a T-type and L-type calcium channel blocker, limits infarct size through a glibenclamide-sensitive mechanism. Cardiovasc Drugs Ther. 1999 Apr;13(2):115-22. [PubMed:10372226]
  3. Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, Nargeot J: Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology. 2000;39(1):1-10. [PubMed:10665814]

Enzymes

Details
1. Cytochrome P450 3A4
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Backman JT, Wang JS, Wen X, Kivisto KT, Neuvonen PJ: Mibefradil but not isradipine substantially elevates the plasma concentrations of the CYP3A4 substrate triazolam. Clin Pharmacol Ther. 1999 Oct;66(4):401-7. doi: 10.1053/cp.1999.v66.a101461. [PubMed:10546924]
  3. Veronese ML, Gillen LP, Dorval EP, Hauck WW, Waldman SA, Greenberg HE: Effect of mibefradil on CYP3A4 in vivo. J Clin Pharmacol. 2003 Oct;43(10):1091-100. doi: 10.1177/0091270003256687. [PubMed:14517191]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Details
3. Cytochrome P450 2D6
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
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. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 11-beta-monooxygenase activity
Specific Function
Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochro...
Gene Name
CYP11B1
Uniprot ID
P15538
Uniprot Name
Cytochrome P450 11B1, mitochondrial
Molecular Weight
57572.44 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 11-beta-monooxygenase activity
Specific Function
Preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone.
Gene Name
CYP11B2
Uniprot ID
P19099
Uniprot Name
Cytochrome P450 11B2, mitochondrial
Molecular Weight
57559.62 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d 24-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Wandel C, Kim RB, Guengerich FP, Wood AJ: Mibefradil is a P-glycoprotein substrate and a potent inhibitor of both P-glycoprotein and CYP3A in vitro. Drug Metab Dispos. 2000 Aug;28(8):895-8. [PubMed:10901697]
  2. Ekins S, Kim RB, Leake BF, Dantzig AH, Schuetz EG, Lan LB, Yasuda K, Shepard RL, Winter MA, Schuetz JD, Wikel JH, Wrighton SA: Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein. Mol Pharmacol. 2002 May;61(5):964-73. [PubMed:11961113]
  3. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. [PubMed:12699389]
  4. Nagy H, Goda K, Fenyvesi F, Bacso Z, Szilasi M, Kappelmayer J, Lustyik G, Cianfriglia M, Szabo G Jr: Distinct groups of multidrug resistance modulating agents are distinguished by competition of P-glycoprotein-specific antibodies. Biochem Biophys Res Commun. 2004 Mar 19;315(4):942-9. [PubMed:14985103]

Drug created on July 06, 2007 14:41 / Updated on September 21, 2018 00:11