Silodosin

Silodosin (known by the trade names Silosoft in India, Urief in Japan, Rapaflo in North America, and Silodyx or Niksol in the European Union[1]) is a medication for the symptomatic treatment of benign prostatic hyperplasia (BPH). It acts as an α1-adrenoceptor antagonist with high uroselectivity (selectivity for the prostate).[2]

Silodosin
Clinical data
Trade namesSilosoft, Urief, Rapaflo, Niksol, Silodyx, others
Other namesKAD-3213, KMD-3213
AHFS/Drugs.comMonograph
MedlinePlusa609002
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability32%
Protein binding96.6%
MetabolismHepatic glucuronidation (UGT2B7-mediated); also minor CYP3A4 involvement
Elimination half-life13±8 hours
Excretion33.5% renal, 54.9% fecal
Identifiers
IUPAC name
  • 1-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]indoline-7-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.248.664
Chemical and physical data
FormulaC25H32F3N3O4
Molar mass495.543 g·mol−1
3D model (JSmol)
SMILES
  • FC(F)(F)COc3ccccc3OCCN[C@H](C)Cc1cc2c(c(c1)C(=O)N)N(CC2)CCCO
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 Y
  • Key:PNCPYILNMDWPEY-QGZVFWFLSA-N Y
 NY (what is this?)  (verify)

Medical uses

Silodosin is used for the treatment of BPH in adult men.[3][4]

Contraindications

According to European labels, silodosin has no contraindications apart from known hypersensitivity.[3][4] Another source names recurring urinary retention, recurring urinary infections, uncontrolled macrohematuria, bladder stones, hydronephrosis, combination with other α1-antagonists or dopamine agonists, and severe renal or hepatic impairment as contraindications.[5] According to the FDA, silodosin is contraindicated with paxlovid, a drug used in treating COVID-19 ( https://www.fda.gov/media/155050/download ).

Side effects

The most common adverse effect is loss of seminal emission. This seems to be caused by silodosin's high selectivity for α1A receptors.[3][6]

Other common adverse effects (in more than 1% of patients) are dizziness, orthostatic hypotension, diarrhoea, and clogged nose. Less common (0.1–1%) are tachycardia (fast heartbeat), dry mouth, nausea, skin reactions, and erectile dysfunction. Hypersensitivity reactions occur in fewer than 0.01% of patients. There have been reports about intraoperative floppy iris syndrome during cataract extractions.[3][4] These side effects are similar to those of other α1 antagonists.

Interactions

Combining silodosin with strong inhibitors of the liver enzyme CYP3A4, such as ketoconazole, significantly increases its concentrations in the blood plasma and its area under the curve (AUC). Less potent CYP3A4 inhibitors such as diltiazem have a less pronounced effect on this parameters, which is not considered clinically significant. Inhibitors and inducers of the enzyme UGT2B7, alcohol dehydrogenases, and aldehyde dehydrogenases, as well as the transporter P-glycoprotein (P-gp), may also influence silodosin concentrations in the body. Digoxin, which is transported by P-gp, is not affected by silodosin; this means that silodosin does not significantly inhibit or induce P-gp.[3][4]

No relevant interactions with antihypertensive drugs or with PDE5 inhibitors have been found in studies; although combination with other α1-antagonists is not well studied.[3][4]

Pharmacology

Mechanism of action

Silodosin has high affinity for the α1A adrenergic receptor in the prostate, the bladder, and the prostatic urethra. By this mechanism it relaxes the smooth muscle in these organs, easing urinary flow and other symptoms of BPH.[2]

Pharmacokinetics

The absolute bioavailability after oral intake is 32%. Food has little effect on the AUC. When in the bloodstream, 96,6% of the substance are bound to blood plasma proteins. Its main metabolite is silodosin glucuronide, which inhibits the α1A receptor with 1/8 of the affinity of the parent substance. 91% of the glucuronide are bound to plasma proteins. The enzyme mainly responsible for the formation of the glucuronide is UGT2B7. Other enzymes involved in the metabolism are alcohol dehydrogenases, aldehyde dehydrogenases and CYP3A4.[1][3]

Silodosin is almost completely excreted in the form of metabolites; 33.5% via the urine and 54.9% via the feces. The biological half-life of silodosin is 11 hours on average, and that of the glucuronide is 18 hours or 24 hours. (Sources are contradictory on this.)[3][4]

  • Silodosin glucuronide
  • KMD-3293, the other main metabolite

History

Silodosin received its first marketing approval in Japan in May 2006, under the brand name Urief, which is jointly marketed by Kissei Pharmaceutical and Daiichi Sankyo.

Kissei licensed the US, Canadian, and Mexican rights for silodosin to Watson Pharmaceuticals (now Allergan) in 2004. AbbVie absorbed Allergan in 2019. The United States Food and Drug Administration and Health Canada approved silodosin under the brand name Rapaflo on 9 October 2008 and 11 January 2011, respectively.[7][8]

Society and culture

Brand names

Other brand names include Urorec (European Union,[9] Australia, Russia), Niksol (Croatia), Silorel (Jamaica),

SiloSoft 'Sildoo, Silodal Silofast (India), Thrupas (South Korea), and Flopadex (Egypt).

Research

As α1A adrenoceptor antagonists are being investigated as a means to male birth control due to their ability to inhibit ejaculation but not orgasm, a trial with 15 male volunteers was conducted. While silodosin was completely efficacious in preventing the release of semen in all subjects, 12 out of the 15 patients reported mild discomfort upon orgasm. The men also reported the psychosexual side effect of being strongly dissatisfied by their lack of ejaculation.[6]

References
  1. "Silodyx EPAR". European Medicines Agency (EMA). 2010-01-10.
  2. FDA Professional Drug Information on Rapaflo. Accessed 2020-01-03.
  3. Haberfeld, H, ed. (2019). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Urorec 4 mg-Hartkapseln.
  4. "Urorec: EPAR – Product Information" (PDF). European Medicines Agency. 2019-11-21.
  5. Dinnendahl, V; Fricke, U, eds. (1982). Arzneistoff-Profile (in German). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
  6. Kobayashi K, Masumori N, Kato R, Hisasue S, Furuya R, Tsukamoto T (December 2009). "Orgasm is preserved regardless of ejaculatory dysfunction with selective alpha1A-blocker administration". Int J Impot Res. 21 (5): 306–10. doi:10.1038/ijir.2009.27. PMC 2834370. PMID 19536124.
  7. "Drugs.com, Watson Announces Silodosin NDA Accepted for Filing by FDA for the Treatment of Benign Prostatic Hyperplasia". Retrieved 2008-02-13.
  8. Health Canada (4 May 2011). "Summary Basis of Decision - Rapaflo". Drug and Health Products Register. Government of Canada. Retrieved 8 January 2021.
  9. "Urorec". European Medicines Agency. 2019-11-21.
  • "Silodosin". Drug Information Portal. U.S. National Library of Medicine.
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