Dutasteride

Dutasteride
Clinical data
Trade names Avodart
AHFS/Drugs.com Monograph
MedlinePlus a603001
Pregnancy
category
  • US: X (Contraindicated)
  • Not to be handled by pregnant women
Routes of
administration		 By mouth
ATC code G04CB02 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 60%
Protein binding 99%
Metabolism Liver (CYP3A4-mediated)
Biological half-life 4 to 5 weeks[1][2]
Excretion Feces
Identifiers
Synonyms GG-745, GI-198745
CAS Number 164656-23-9 YesY
PubChem (CID) 6918296
IUPHAR/BPS 7457
DrugBank DB01126 YesY
ChemSpider 5293502 YesY
UNII O0J6XJN02I YesY
KEGG D03820 YesY
ChEBI CHEBI:521033 YesY
ChEMBL CHEMBL1200969 N
Chemical and physical data
Formula C27H30F6N2O2
Molar mass 528.53 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Dutasteride, sold under the brand name Avodart among others, is a medication used to treat benign prostatic hyperplasia (enlarged prostate) and androgenetic alopecia (pattern hair loss).[3]

It was developed by GlaxoSmithKline[4] and is a 5α-reductase inhibitor which prevents the conversion of the androgen sex hormone testosterone into the more potent dihydrotestosterone (DHT).[5] The drug has been licensed for the treatment of androgenetic alopecia in South Korea since 2009, but has not been approved for this indication in the United States,[6][7] though it is commonly used off-label.[8]

Medical uses

Avodart (dutasteride) 500 µg soft capsules

Prostate enlargement

Dutasteride is useful for treating benign prostatic hyperplasia (BPH); colloquially known as an "enlarged prostate".[3][9]

Prostate cancer

In those who are being regularly screened, 5α-reductase inhibitors such as finasteride and dutasteride reduce the overall risk of being diagnosed with prostate cancer; however, there is insufficient data to determine if they have an effect on the risk of death and may increase the chance of more serious cases.[10]

Pattern hair loss

Dutasteride is approved for the treatment of male androgenetic alopecia in South Korea at a dosage of 0.5 mg per day.[6][7] It has been found in several studies to improve hair growth in men more rapidly and to a greater extent than 2.5 mg/day finasteride.[6] Dutasteride has also been used off-label in the treatment of female pattern hair loss.[8]

Adverse effects

Dutasteride has been found to be well-tolerated in clinical studies in both men and women, producing minimal side effects.[11] Sexual dysfunction, including erectile dysfunction, loss of libido, and reduced ejaculate may occur in 3.4 to 15.8% of men treated with the drug.[11] Several small studies have reported an association between 5α-reductase inhibitors and depression.[11] However, most studies have not observed this side effect, and a direct link has yet been established.[11] There have also been reports in a subset of men of long-lasting sexual dysfunction and depression persisting even after discontinuation of dutasteride.[11][12] Other general side effects include headache and gastrointestinal discomfort.[11] Isolated reports of menstrual changes, acne, and dizziness also exist.[11] There is a very small risk of gynecomastia (breast enlargement) in men.[11] In pregnant women, dutasteride can cause birth defects in male fetuses, namely ambiguous genitalia, and for this reason, should never be given to them.[11]

Sexual dysfunction

This class of medications increases rates of erectile dysfunction (with between 3.4 and 15.8% developing problems after starting their use).[11] This is linked to lower quality of life and can cause stress in relationships.[13] There is also an association with lowered sexual desire.[12] It has been reported that these adverse sexual side effects may persist even after discontinuation of the drug in a subset of men.[12]

Prostate cancer

The FDA has added a warning to dutasteride about an increased risk of high-grade prostate cancer.[14] While the potential for positive, negative or neutral changes to the potential risk of developing prostate cancer with dutasteride has not been established, evidence has suggested it may temporarily reduce the growth and prevalence of benign prostate tumors, but could also mask the early detection of prostate cancer. The primary area for concern is for patients who may develop prostate cancer whilst taking dutasteride for benign prostatic hyperplasia, which in turn could delay diagnosis and early treatment of the prostate cancer, thereby potentially increasing the risk of these patients developing high-grade prostate cancer.[15]

Contraindications

Children and women who are or may become pregnant, and people with known significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride or finasteride should not take dutasteride. Exposure to dutasteride and other 5α-reductase inhibitors during pregnancy can cause birth defects. Since these medications are readily absorbed through the skin, women who are or may become pregnant should not handle them and if they come into contact with leaking capsules, the contact area should be washed immediately in soapy water. People taking dutasteride should not donate blood and, due to its long half-life, should also not donate blood for at least 6 months after the cessation of treatment.[16]

Mechanism of action

Dutasteride belongs to a class of drugs called 5α-reductase inhibitors, which block the action of the 5α-reductase enzymes that convert testosterone into DHT.[17] It is an irreversible inhibitor of all three isoforms of 5α-reductase, types I, II, and III.[5][18][19] This is in contrast to finasteride, which is similarly an irreversible inhibitor of 5α-reductase[19][20] but only inhibits the type II and III isoenzymes.[5] As a result of this difference, dutasteride is able to achieve a reduction in circulating DHT levels of as much as 98%, whereas finasteride is only able to achieve a reduction of 65 to 70%.[21][1][17][22] In spite of the differential reduction in circulating DHT levels, the two drugs decrease levels of DHT to a similar extent (approximately 85 to 90%) in the prostate gland,[22] where the type II isoform of 5α-reductase predominates.[18]

In addition to DHT, dutasteride prevents the 5α-reductase-mediated formation of neurosteroids such as allopregnanolone and THDOC, and 3α-androstanediol (see also neurosteroidogenesis inhibitor).[23] These neurosteroids are potent positive allosteric modulators of the GABAA receptor and have been found to possess antidepressant, anxiolytic, and pro-sexual effects in animal research.[23][24][25] For this reason, prevention of neurosteroid formation may be responsible for the sexual dysfunction and depression that has been associated with 5α-reductase inhibitors like dutasteride.[23]

Pharmacokinetics

Dutasteride has an extremely long terminal half-life of four or five weeks.[1][2] For this reason, it takes months for dutasteride to be eliminated from the body after discontinuation.[1] In contrast to dutasteride, the terminal half-life of finasteride is short, at only 6 to 8 hours.[2]

Chemistry

Dutasteride is a 4-azasteroid.[26][27] It is an analogue of finasteride in which the t-butyl amide moiety has been replaced with a 2,5-bis(trifluoromethyl)phenyl group.[27]

Society and culture

FDA approval

Dutasteride is approved by the Food and Drug Administration (FDA) for treatment of benign prostatic hyperplasia.[28]

Research

Premenstrual symptoms

A study found that dutasteride, which blocks the formation of the neurosteroid allopregnanolone from progesterone, is effective in reducing symptoms in women with premenstrual dysphoric disorder.[29]

References

  1. 1 2 3 4 Jacqueline Burchum; Laura Rosenthal (2 December 2014). Lehne's Pharmacology for Nursing Care. Elsevier Health Sciences. pp. 803–. ISBN 978-0-323-34026-7.
  2. 1 2 3 Ulrike Blume-Peytavi; David A. Whiting; Ralph M. Trüeb (26 June 2008). Hair Growth and Disorders. Springer Science & Business Media. pp. 182–. ISBN 978-3-540-46911-7.
  3. 1 2 Wu C, Kapoor A (2013). "Dutasteride for the treatment of benign prostatic hyperplasia". Expert Opin Pharmacother. 14 (10): 1399–408. doi:10.1517/14656566.2013.797965. PMID 23750593.
  4. ↑ http://www.tevapharm.com/news/teva_announces_exclusive_launch_of_generic_avodart_capsules_in_the_united_states_10_15.aspx
  5. 1 2 3 Yamana K, Labrie F, Luu-The V (January 2010). "Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride". Hormone Molecular Biology and Clinical Investigation. 2 (3). doi:10.1515/hmbci.2010.035.
  6. 1 2 3 Jerry Shapiro; Nina Otberg (17 April 2015). Hair Loss and Restoration, Second Edition. CRC Press. pp. 39–. ISBN 978-1-4822-3199-1.
  7. 1 2 Choi GS, Kim JH, Oh SY, Park JM, Hong JS, Lee YS, Lee WS (2016). "Safety and Tolerability of the Dual 5-Alpha Reductase Inhibitor Dutasteride in the Treatment of Androgenetic Alopecia". Ann Dermatol. 28 (4): 444–50. doi:10.5021/ad.2016.28.4.444. PMC 4969473Freely accessible. PMID 27489426.
  8. 1 2 Nusbaum AG, Rose PT, Nusbaum BP (2013). "Nonsurgical therapy for hair loss". Facial Plast Surg Clin North Am. 21 (3): 335–42. doi:10.1016/j.fsc.2013.04.003. PMID 24017975.
  9. ↑ Slater, S; Dumas, C; Bubley, G (March 2012). "Dutasteride for the treatment of prostate-related conditions.". Expert opinion on drug safety. 11 (2): 325–30. doi:10.1517/14740338.2012.658040. PMID 22316171.
  10. ↑ Wilt TJ, MacDonald R, Hagerty K, Schellhammer P, Kramer BS (2008). "Five-alpha-reductase Inhibitors for prostate cancer prevention". Cochrane Database Syst Rev (2): CD007091. doi:10.1002/14651858.CD007091. PMID 18425978.
  11. 1 2 3 4 5 6 7 8 9 10 Hirshburg JM, Kelsey PA, Therrien CA, Gavino AC, Reichenberg JS (2016). "Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review". J Clin Aesthet Dermatol. 9 (7): 56–62. PMC 5023004Freely accessible. PMID 27672412.
  12. 1 2 3 Traish, AM; Hassani, J; Guay, AT; Zitzmann, M; Hansen, ML (March 2011). "Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients.". The journal of sexual medicine. 8 (3): 872–84. doi:10.1111/j.1743-6109.2010.02157.x. PMID 21176115.
  13. ↑ Gur, S; Kadowitz, PJ; Hellstrom, WJ (January 2013). "Effects of 5-alpha reductase inhibitors on erectile function, sexual desire and ejaculation.". Expert opinion on drug safety. 12 (1): 81–90. doi:10.1517/14740338.2013.742885. PMID 23173718.
  14. ↑ 5-alpha reductase inhibitors (5-ARIs): Label Change - Increased Risk of Prostate Cancer | U.S. Department of Health & Human Services
  15. ↑ Walsh, PC (Apr 1, 2010). "Chemoprevention of prostate cancer.". The New England Journal of Medicine. 362 (13): 1237–8. doi:10.1056/NEJMe1001045. PMID 20357287.
  16. ↑ "FDA prescribing information" (PDF). June 2011. Retrieved 15 September 2013.
  17. 1 2 David G. Bostwick; Liang Cheng (24 January 2014). Urologic Surgical Pathology. Elsevier Health Sciences. pp. 492–. ISBN 978-0-323-08619-6.
  18. 1 2 Keam SJ, Scott LJ (2008). "Dutasteride: a review of its use in the management of prostate disorders". Drugs. 68 (4): 463–85. PMID 18318566.
  19. 1 2 Gisleskog PO, Hermann D, Hammarlund-Udenaes M, Karlsson MO (1998). "A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors GI198745 and finasteride". Clin. Pharmacol. Ther. 64 (6): 636–47. doi:10.1016/S0009-9236(98)90054-6. PMID 9871428.
  20. ↑ György Keserü; David C. Swinney (28 July 2015). Thermodynamics and Kinetics of Drug Binding. Wiley. pp. 165–. ISBN 978-3-527-67304-9.
  21. ↑ Rob Bradbury (30 January 2007). Cancer. Springer Science & Business Media. pp. 49–. ISBN 978-3-540-33120-9.
  22. 1 2 John Heesakkers; Christopher Chapple; Dirk De Ridder; Fawzy Farag (24 February 2016). Practical Functional Urology. Springer. pp. 280–. ISBN 978-3-319-25430-2.
  23. 1 2 3 Traish AM, Mulgaonkar A, Giordano N (2014). "The dark side of 5α-reductase inhibitors' therapy: sexual dysfunction, high Gleason grade prostate cancer and depression". Korean J Urol. 55 (6): 367–79. doi:10.4111/kju.2014.55.6.367. PMC 4064044Freely accessible. PMID 24955220.
  24. ↑ Abraham Weizman (1 February 2008). Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders: Novel Strategies for Research and Treatment. Springer Science & Business Media. ISBN 978-1-4020-6854-6.
  25. ↑ Tvrdeić, Ante; Poljak, Ljiljana (2016). "Neurosteroids, GABAA receptors and neurosteroid based drugs: are we witnessing the dawn of the new psychiatric drugs?". Endocrine Oncology and Metabolism. 2 (1): 60–71. doi:10.21040/eom/2016.2.7. ISSN 1849-8922.
  26. ↑ Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1381–. ISBN 978-1-60913-345-0.
  27. 1 2 Enrique Ravina (11 January 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. pp. 183–. ISBN 978-3-527-32669-3.
  28. ↑ http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=021319&DrugName=AVODART&ActiveIngred=DUTASTERIDE&SponsorApplicant=GLAXOSMITHKLINE&ProductMktStatus=1&goto=Search.DrugDetails
  29. ↑ Pearlstein T (2016). "Treatment of Premenstrual Dysphoric Disorder: Therapeutic Challenges". Expert Rev Clin Pharmacol: 1–4. doi:10.1586/17512433.2016.1142371. PMID 26766596.
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