Identification

Name
Silodosin
Accession Number
DB06207
Type
Small Molecule
Groups
Approved
Description

Silodosin is an α1-adrenoceptor antagonist that is selective for the prostate. Silodosin is for symptomatic treatment of benign prostatic hyperplasia. FDA approved Oct 9, 2008.

Structure
Thumb
Synonyms
  • KAD 3213
  • KMD 3213
  • Urief
External IDs
KAD-3213 / KMD-3213
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RapafloCapsule8 mgOralAllergan2011-10-26Not applicableCanada
RapafloCapsule8 mg/1OralAvera McKennan Hospital2015-03-23Not applicableUs69189 016920180907 15195 moe69n
RapafloCapsule8 mg/1OralActavis Pharma Company2009-03-23Not applicableUs52544 0152 30 nlmimage10 041c8214
RapafloCapsule4 mgOralAllergan2011-10-26Not applicableCanada
RapafloCapsule4 mg/1OralAllergan2009-03-23Not applicableUs
RapafloCapsule4 mg/1OralAvera McKennan Hospital2015-05-01Not applicableUs69189 021520180907 15195 11uj4nw
RapafloCapsule8 mg/1OralPhysicians Total Care, Inc.2010-09-15Not applicableUs54868 617320180907 15195 1vf14n6
RapafloCapsule8 mg/1OralAllergan2009-03-23Not applicableUs
RapafloCapsule4 mg/1OralActavis Pharma Company2009-03-23Not applicableUs52544 0151 30 nlmimage10 343e9a24
SilodyxCapsule4 mgOralRecordati Ireland Ltd2010-01-29Not applicableEu
International/Other Brands
Rapaflo / Rapilif (Ipca Urosciences ) / Silodyx (Recordati Industria Chimica e Farmaceutica S.p.A.) / Urief (Watson Pharmaceuticals Inc.)
Categories
UNII
CUZ39LUY82
CAS number
160970-54-7
Weight
Average: 495.5345
Monoisotopic: 495.234491142
Chemical Formula
C25H32F3N3O4
InChI Key
PNCPYILNMDWPEY-QGZVFWFLSA-N
InChI
InChI=1S/C25H32F3N3O4/c1-17(30-8-12-34-21-5-2-3-6-22(21)35-16-25(26,27)28)13-18-14-19-7-10-31(9-4-11-32)23(19)20(15-18)24(29)33/h2-3,5-6,14-15,17,30,32H,4,7-13,16H2,1H3,(H2,29,33)/t17-/m1/s1
IUPAC Name
1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide
SMILES
C[C@H](CC1=CC2=C(N(CCCO)CC2)C(=C1)C(N)=O)NCCOC1=CC=CC=C1OCC(F)(F)F

Pharmacology

Indication

Treatment for symptomatic relief of benign prostatic hyperplasia

Associated Conditions
Pharmacodynamics

Silodosin is 583 times more selective for human alpha-1A receptors than alpha-1B receptors. It is also 56 times more selective for human alpha-1A receptors than alpha-1D. Silodosin does not prolong the QT interval.

Mechanism of action

Benign prostate hyperplasia (BPH), or an enlarged prostate, is a condition found only in men and is characterized by a non-cancerous enlargement of the prostate gland. Symptoms of BPH include urinary difficulty, urinary frequency and an inability to complete bladder emptying. Silodosin is highly uroselective for the alpha (1A) receptors located in the prostate, [urethrea and bladder trigone in the lower urinary tract]. Blocking these receptors relaxes the smooth muscles, resulting in an improvement in urine flow and a reduction in BPH symptoms. The selective binding of silodosin to the alpha (1A) receptors is substantially greater than the binding to the cardiovascular-associated alpha (1B) receptors and thereby maximizes target organ activity while minimizing the potential for blood pressure effects. [Watson Pharmaceutical Inc. Press release] Silodosin is alpha 1A-adrenoceptor selective antagonist which inhibits sympathetic nerve stimulation and relaxation of smooth muscle tone in the lower urinary tract which relieves the pressure from contraction of smooth muscle. The reduction of intraurethral pressure improves voiding and storage issues associated with BPH.

TargetActionsOrganism
AAlpha-1A adrenergic receptor
antagonist
Human
UAlpha-1B adrenergic receptor
antagonist
Human
UAlpha-1D adrenergic receptor
antagonist
Human
Absorption

Quickly absorbed and has a bioavailability of 32% at 8mg/day (therapeutic dose). When 8 mg of silodosin is taken once daily with food, the pharmacokinetic parameters are as follows: Cmax = 61.6 ± 27.54 ng/mL; Tmax = 2.6 ± 0.90 hours;
AUC (0h-24h) = 373 ng•hr/ml. The AUC of its metabolite, KMD3213G, is four times greater than silodosin.

Volume of distribution

49.5 L

Protein binding

97% bound to protein

Metabolism

Extensively metabolized in the liver. The main metabolite is generated via glucuronidation (KMD-3213G) by UDP-2B7. Oxidation by alcohol and aldehyde dehydrogenases produces the second major metabolite, KMD-3293. KMD-3213G accumulates in the plasma as it is very hydrophilic. KMD-3213G is also an active metabolite in which it has 50% of silodosin's inhibitory activity. KMD-3293 is inactive. Cytochrome P450 CYP 3A4 also generates some metabolites.

Route of elimination

Fecal (54.9%);
Renal (33.5%)

Half life

Silodosin = 13.3 ± 8.07 hours; KMD-3213G = 24 hours;

Clearance

Plasma clearance = 10 L/h

Toxicity

Most common adverse reactions (incidence > 2%) are retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, and nasal congestion.

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

Interactions

Drug Interactions
DrugInteraction
4-MethoxyamphetamineSilodosin may decrease the vasoconstricting activities of 4-Methoxyamphetamine.
AbemaciclibThe serum concentration of Silodosin can be increased when it is combined with Abemaciclib.
AcebutololAcebutolol may increase the orthostatic hypotensive activities of Silodosin.
AcepromazineSilodosin may increase the antihypertensive activities of Acepromazine.
AcetaminophenThe serum concentration of Silodosin can be increased when it is combined with Acetaminophen.
Acetyl sulfisoxazoleThe metabolism of Silodosin can be decreased when combined with Acetyl sulfisoxazole.
AdrafinilSilodosin may decrease the vasoconstricting activities of Adrafinil.
AfatinibThe serum concentration of Silodosin can be increased when it is combined with Afatinib.
AgmatineThe therapeutic efficacy of Agmatine can be decreased when used in combination with Silodosin.
AlbendazoleThe serum concentration of Silodosin can be increased when it is combined with Albendazole.
Food Interactions
  • The effect of a moderate fat, moderate calorie meal was variable and decreased silodosin Cmax by approximately 18 − 43% and AUC by 4 − 49%

References

General References
  1. Yoshida M, Homma Y, Kawabe K: Silodosin, a novel selective alpha 1A-adrenoceptor selective antagonist for the treatment of benign prostatic hyperplasia. Expert Opin Investig Drugs. 2007 Dec;16(12):1955-65. [PubMed:18042003]
  2. Yamada S, Kato Y, Okura T, Kagawa Y, Kawabe K: Prediction of alpha1-adrenoceptor occupancy in the human prostate from plasma concentrations of silodosin, tamsulosin and terazosin to treat urinary obstruction in benign prostatic hyperplasia. Biol Pharm Bull. 2007 Jul;30(7):1237-41. [PubMed:17603160]
External Links
KEGG Drug
D01965
PubChem Compound
5312125
PubChem Substance
175427058
ChemSpider
4471557
BindingDB
50160154
ChEBI
135929
ChEMBL
CHEMBL24778
PharmGKB
PA165291889
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Silodosin
ATC Codes
G04CA04 — Silodosin
AHFS Codes
  • 12:16.04.12 — Selective Alfa-1-adrenergic Blocking Agents
FDA label
Download (846 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentAbacterial Chronic Prostatitis/Chronic Pelvic Pain Syndrome1
2CompletedTreatmentBenign Prostatic Hyperplasia (BPH)1
2CompletedTreatmentNocturia / Prostatic Hyperplasia1
2CompletedTreatmentRenal Stones / Ureteral Calculus / Urolithiasis1
2CompletedTreatmentUrinary Tract Stones1
2RecruitingTreatmentPremature Ejaculation1
3CompletedTreatmentBenign Prostatic Hyperplasia (BPH)4
3RecruitingSupportive CareProstate Cancer / Urinary Problems1
3TerminatedTreatmentExpulsive Medical Therapy / Renal Stones1
3WithdrawnTreatmentRenal Stones1
4CompletedTreatmentBenign Prostatic Hyperplasia (BPH)2
4CompletedTreatmentBenign Prostatic Hyperplasia (BPH) / Nocturia1
4CompletedTreatmentBenign Prostatic Hypertrophy (BPH)1
4CompletedTreatmentNeurogenic Bladder Dysfunction / Voiding Dysfunction1
4CompletedTreatmentUreteral Stones1
4TerminatedTreatmentUreteral Calculus / Ureteral Stones / Ureterolithiasis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral4 mg/1
CapsuleOral8 mg/1
CapsuleOral4 mg
CapsuleOral8 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5403847No1992-11-132012-11-13Us
US5387603No1998-12-012018-12-01Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)105 - 109°CFDA label
water solubilityVery slightly soluble FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.0111 mg/mLALOGPS
logP2.96ALOGPS
logP3.05ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)14.87ChemAxon
pKa (Strongest Basic)9.66ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area97.05 Å2ChemAxon
Rotatable Bond Count14ChemAxon
Refractivity128.92 m3·mol-1ChemAxon
Polarizability49.89 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.7383
Caco-2 permeable-0.5847
P-glycoprotein substrateSubstrate0.8467
P-glycoprotein inhibitor INon-inhibitor0.5833
P-glycoprotein inhibitor IIInhibitor0.7864
Renal organic cation transporterNon-inhibitor0.7288
CYP450 2C9 substrateNon-substrate0.8226
CYP450 2D6 substrateNon-substrate0.6362
CYP450 3A4 substrateSubstrate0.6585
CYP450 1A2 substrateNon-inhibitor0.7439
CYP450 2C9 inhibitorNon-inhibitor0.7569
CYP450 2D6 inhibitorNon-inhibitor0.5958
CYP450 2C19 inhibitorNon-inhibitor0.5562
CYP450 3A4 inhibitorInhibitor0.7424
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5723
Ames testNon AMES toxic0.6667
CarcinogenicityNon-carcinogens0.8529
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.4845 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.98
hERG inhibition (predictor II)Inhibitor0.8366
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-0121090000-11833eeb1f3c76d92dda
MS/MS Spectrum - , positiveLC-MS/MSsplash10-01ot-1490800000-2175bd3c7bc607b74fee
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000x-1980000000-5d01eb798b6009518223

Taxonomy

Description
This compound belongs to the class of organic compounds known as indolecarboxamides and derivatives. These are compounds containing a carboxamide group attached to an indole.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Indolecarboxylic acids and derivatives
Direct Parent
Indolecarboxamides and derivatives
Alternative Parents
Dialkylarylamines / Phenol ethers / Phenoxy compounds / Alkyl aryl ethers / Aralkylamines / Vinylogous amides / 1,3-aminoalcohols / Amino acids and derivatives / Primary carboxylic acid amides / Dialkylamines
show 7 more
Substituents
Indolecarboxamide derivative / Phenoxy compound / Phenol ether / Tertiary aliphatic/aromatic amine / Dialkylarylamine / Alkyl aryl ether / Aralkylamine / Monocyclic benzene moiety / Benzenoid / Vinylogous amide
show 26 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1A
Uniprot ID
P35348
Uniprot Name
Alpha-1A adrenergic receptor
Molecular Weight
51486.005 Da
References
  1. Lepor H, Hill LA: Silodosin for the treatment of benign prostatic hyperplasia: pharmacology and cardiovascular tolerability. Pharmacotherapy. 2010 Dec;30(12):1303-12. doi: 10.1592/phco.30.12.1303. [PubMed:21114397]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1B
Uniprot ID
P35368
Uniprot Name
Alpha-1B adrenergic receptor
Molecular Weight
56835.375 Da
References
  1. Lepor H, Hill LA: Silodosin for the treatment of benign prostatic hyperplasia: pharmacology and cardiovascular tolerability. Pharmacotherapy. 2010 Dec;30(12):1303-12. doi: 10.1592/phco.30.12.1303. [PubMed:21114397]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Alpha1-adrenergic receptor activity
Specific Function
This alpha-adrenergic receptor mediates its effect through the influx of extracellular calcium.
Gene Name
ADRA1D
Uniprot ID
P25100
Uniprot Name
Alpha-1D adrenergic receptor
Molecular Weight
60462.205 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
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. Matsubara Y, Kanazawa T, Kojima Y, Abe Y, Kobayashi K, Kanbe H, Harada H, Momose Y, Terakado S, Adachi Y, Midgley I: [Pharmacokinetics and disposition of silodosin (KMD-3213)]. Yakugaku Zasshi. 2006 Mar;126 Spec no.:237-45. [PubMed:16518089]
  2. Cantrell MA, Bream-Rouwenhorst HR, Hemerson P, Magera JS Jr: Silodosin for benign prostatic hyperplasia. Ann Pharmacother. 2010 Feb;44(2):302-10. doi: 10.1345/aph.1M320. Epub 2010 Jan 13. [PubMed:20071497]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
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. Matsubara Y, Kanazawa T, Kojima Y, Abe Y, Kobayashi K, Kanbe H, Harada H, Momose Y, Terakado S, Adachi Y, Midgley I: [Pharmacokinetics and disposition of silodosin (KMD-3213)]. Yakugaku Zasshi. 2006 Mar;126 Spec no.:237-45. [PubMed:16518089]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion. Functions as a floppase that translocates specifically phosphatidylcholine (PC) from ...
Gene Name
ABCB4
Uniprot ID
P21439
Uniprot Name
Phosphatidylcholine translocator ABCB4
Molecular Weight
141521.845 Da
References
  1. Matsubara Y, Kanazawa T, Kojima Y, Abe Y, Kobayashi K, Kanbe H, Harada H, Momose Y, Terakado S, Adachi Y, Midgley I: [Pharmacokinetics and disposition of silodosin (KMD-3213)]. Yakugaku Zasshi. 2006 Mar;126 Spec no.:237-45. [PubMed:16518089]

Drug created on March 19, 2008 10:17 / Updated on September 22, 2018 22:34