Dutasteride

Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of an enlarged prostate.[4][5] A few months may be required before benefits occur.[5] It is also used for scalp hair loss in men and as a part of hormone therapy in transgender women.[6][7] It is taken by mouth.[4][8]

Dutasteride
Clinical data
Trade namesAvodart, others; Combodart, Duodart (with tamsulosin)
Other namesGG-745; GI-198745; GI-198745X; N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide
AHFS/Drugs.comMonograph
MedlinePlusa603001
License data
Pregnancy
category
  • US: X (Contraindicated)
  • Not to be used during pregnancy
Routes of
administration		By mouth
Drug class5α-Reductase inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60%[1]
Protein binding99%[1]
MetabolismLiver (CYP3A4)[1]
Metabolites• 4'-Hydroxydutasteride[1]
• 6'-Hydroxydutasteride[1]
• 1,2-Dihydrodutasteride[1]
(All three active)[1]
Elimination half-life4–5 weeks[2][3]
ExcretionFeces: 40% (metabolites)[1]
Urine: 5% (unchanged)[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.166.372
Chemical and physical data
FormulaC27H30F6N2O2
Molar mass528.539 g·mol−1
3D model (JSmol)
  (verify)

Common side effects include sexual problems, breast tenderness, and breast enlargement.[4] Other side effects include an increased risk of certain forms of prostate cancer, depression, and angioedema.[4][5] Exposure during pregnancy, including use by the partner of a pregnant women may result in harm to the baby.[4][5] Dutasteride is a 5α-reductase inhibitor, and hence is a type of antiandrogen.[3] It works by decreasing the production of dihydrotestosterone (DHT), an androgen sex hormone.[9][4]

Dutasteride was patented in 1993 by GlaxoSmithKline and was approved for medical use in 2001.[10][4] It is available as a generic medication.[5] A month supply in the United Kingdom costs the NHS about £12 as of 2019.[5] In the United States, the wholesale cost of this amount is about $6.66.[11] In 2017, it was the 276th most commonly prescribed medication in the United States, with more than one million prescriptions.[12][13]

Medical uses

Enlarged prostate

Dutasteride is used for treating benign prostatic hyperplasia (BPH); colloquially known as an "enlarged prostate".[8][14] It is approved by the Food and Drug Administration (FDA) in the U.S. for this indication.[15]

Prostate cancer

A 2010 Cochrane review found a 25–26% reduction in the risk of developing prostate cancer with 5α-reductase inhibitor chemoprevention.[16] However, 5α-reductase inhibitors have been found to increase the risk of developing certain rare but aggressive forms of prostate cancer (27% risk increase), although not all studies have observed this.[17] There is insufficient data to determine if they have an effect on the overall risk of death from prostate cancer.[17]

Scalp hair loss

Dutasteride is approved for the treatment of male androgenetic alopecia in South Korea and Japan at a dosage of 0.5 mg per day.[6][18] 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] The superior effectiveness of dutasteride relative to finasteride for this indication is considered to be related to the fact that the inhibition of 5α-reductase and consequent prevention of scalp DHT production is more complete with dutasteride.[1][19] Dutasteride is also used off-label in the treatment of female pattern hair loss.[20][21]

Excessive hair growth

Although no reports specific to dutasteride currently exist,[22][3] 5α-reductase inhibitors like finasteride have been found to be effective in the treatment of hirsutism (excessive facial and/or body hair growth) in women.[3] In a study of 89 women with hyperandrogenism due to persistent adrenarche syndrome, finasteride produced a 93% reduction in facial hirsutism and a 73% reduction in bodily hirsutism after 2 years of treatment.[3] Other studies using finasteride for hirsutism have also found it to be clearly effective.[3] Dutasteride may be more effective than finasteride for this indication due to the fact that its inhibition of the 5α-reductase enzyme is comparatively more complete.[1]

Transgender hormone therapy

Dutasteride is sometimes used as a component of hormone therapy for transgender women in combination with an estrogen and/or another antiandrogen like spironolactone.[7] It may be useful for treating scalp hair loss or in those who have issues tolerating spironolactone.[7]

Available forms

Dutasteride is provided in the form of soft oil-filled gelatin oral capsules containing 0.5 mg dutasteride each.[23]

Contraindications

Women who are or who may become pregnant should not handle the drug. Dutasteride can cause birth defects, specifically ambiguous genitalia and undermasculinization, in male fetuses.[23][24] This is due to its antiandrogenic effects and is seen naturally in 5α-reductase deficiency.[24] As such, women who are pregnant should never take dutasteride.[23] People taking dutasteride should not donate blood to prevent birth defects if a pregnant women receives blood and, due to its long elimination half-life, should also not donate blood for at least 6 months after the cessation of treatment.[23]

Children and people with known significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride should not take dutasteride.[23]

Adverse effects

Dutasteride has overall been found to be well tolerated in studies of both men and women, producing minimal side effects.[17] Adverse effects include headache and gastrointestinal discomfort.[17] Isolated reports of menstrual changes, acne, and dizziness also exist.[17] There is a small risk of gynecomastia (breast development or enlargement) in men.[17] The risk of gynecomastia with 5α-reductase inhibitors is about 2.8%.[25]

The FDA has added a warning to dutasteride about an increased risk of high-grade prostate cancer.[26] 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.[27] A 2018 meta-analysis found no higher risk of breast cancer with 5α-reductase inhibitors.[28]

Sexual dysfunction, such as erectile dysfunction, loss of libido, or reduced semen volume, may occur in 3.4 to 15.8% of men treated with finasteride or dutasteride.[17][29] This is linked to lower quality of life and can cause stress in relationships.[30] It has been reported that in a subset of men, these adverse sexual side effects may persist even after discontinuation of finasteride or dutasteride.[31] Some have decreased sperm numbers as low as 10% of pretreatment values.[32]

Several small studies have reported an association between 5α-reductase inhibitors and depression.[17] However, most studies have not observed this side effect.[17] There have also been reports in a subset of men of long-lasting depression persisting even after discontinuation of dutasteride.[17][31]

Overdose

There is no specific antidote for overdose of dutasteride.[33] Treatment of dutasteride overdose should be based on symptoms and should be supportive.[33] The long elimination half-life of dutasteride should be taken into consideration in the event of an overdose of the medication.[33] Dutasteride has been used in clinical studies at doses of up to 40 mg/day for a week (80 times the therapeutic dosage) and 5 mg/day for 6 months (10 times the therapeutic dosage) with no significant safety concerns or additional side effects, respectively.[33]

Interactions

5α-Reductase inhibitors can also prevent the formation of neurosteroid metabolites like allopregnanolone from progesterone and hence may reduce or block the sedative, anticonvulsant, anxiolytic, and various other effects of progesterone, particularly in the case of oral progesterone (which is disproportionately converted into these metabolites due to first-pass metabolism).[34][35][36][37][38]

Pharmacology

Pharmacodynamics

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.[39] It inhibits all three forms of 5α-reductase, and can decrease DHT levels in the blood by up to 98%.[1][40][41] Specifically it is a competitive, mechanism-based (irreversible) inhibitor of all three isoforms of 5α-reductase, types I, II, and III (IC50 values are 3.9 nM for type I and 1.8 nM for type II).[1][40][42][43] This is in contrast to finasteride, which is similarly an irreversible inhibitor of 5α-reductase[43][44] but only inhibits the type II and III isoenzymes.[40] As a result of this difference, dutasteride is able to achieve a reduction in circulating DHT levels of up to 98%, whereas finasteride is able to achieve a reduction of only 65 to 70%.[41][2][39][45] In spite of the differential reduction in circulating DHT levels, the two drugs decrease levels of DHT to a similar extent of approximately 85 to 90% in the prostate gland,[45] where the type II isoform of 5α-reductase predominates.[42]

Since 5α-reductases degrade testosterone to DHT, the inhibition of them could cause an increase in testosterone. However, a 2018 review found that initiation of 5α-reductase inhibitors did not result in a consistent increase in testosterone levels, with some studies showing increases and others showing no change.[46] There was no statistically significant change in testosterone levels from 5α-reductase inhibitors in the overall meta-analysis, though men with lower baseline testosterone levels may a rise in testosterone levels.

In addition to inhibition of DHT production, 5α-reductase inhibitors like dutasteride are also neurosteroidogenesis inhibitors, preventing the 5α-reductase-mediated biosynthesis of various neurosteroids including allopregnanolone (from progesterone), THDOC (from deoxycorticosterone), and 3α-androstanediol (from testosterone).[47] 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.[47][48][49] For this reason, prevention of neurosteroid formation may be involved in the sexual dysfunction and depression that has been associated with 5α-reductase inhibitors like dutasteride.[47]

Pharmacokinetics

The oral bioavailability of dutasteride is approximately 60%.[1] Food does not adversely affect the absorption of dutasteride.[1] Peak plasma levels occur 2 to 3 hours after administration.[1] Levels of dutasteride in semen have been found to be 3 ng/mL, with no significant effects on DHT levels in sexual partners.[1] The drug is extensively metabolized in the liver by CYP3A4.[1] It has three major metabolites, including 6'-hydroxydutasteride, 4'-hydroxydutasteride, and 1,2-dihydrodutasteride; the former two are formed by CYP3A4, while the latter is not.[1] All three metabolites are active; 6'-hydroxydutasteride has similar potency as a 5α-reductase inhibitor to dutasteride, while the other two are less potent.[1] Dutasteride has an extremely long terminal or elimination half-life of about 4 or 5 weeks.[2][3] The elimination half-life of dutasteride is increased in the elderly (170 hours for men age 20–49 years, 300 hours for men age >70 years).[1] No dosage adjustment is necessary in the elderly nor in renal impairment.[1] Because of its long elimination half-life, dutasteride remains in the body for a long time after discontinuation and can be detected for up to 4 to 6 months.[1][2] In contrast to dutasteride, finasteride has a short terminal half-life of only 5 to 8 hours.[3][1] Dutasteride is eliminated mainly in the feces (40%) as metabolites.[1] A small portion (5%) is eliminated unchanged in the urine.[1]

Chemistry
See also: List of 5α-reductase inhibitors

Dutasteride, also known as N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, is a synthetic androstane steroid and a 4-azasteroid.[50][51] It is an analogue of finasteride in which the tert-butyl amide moiety has been replaced with a 2,5-bis(trifluoromethyl)phenyl group.[51]

History

Dutasteride was patented in 1996[52] and was first described in the scientific literature in 1997.[53] It was approved by the FDA for the treatment of BPH in November 2001 and was introduced into the United States market the following year under the brand name Avodart.[53] Dutasteride has subsequently been introduced in many other countries, including throughout Europe and South America.[53] The patent protection of dutasteride expired in November 2015 and the drug has since become available in the United States in a variety of low-cost generic formulations.[52]

It was approved for the treatment of scalp hair loss in South Korea since 2009 and in Japan since 2015.[54] It has not been approved for this indication in the United States,[6][18] though it is often used off-label.[20]

Society and culture
Avodart (dutasteride) 500 µg soft capsules.

Generic names

Dutasteride is the generic name of the drug and its INN, USAN, BAN, and JAN.[55]

Brand names

Dutasteride is sold primarily under the brand name Avodart and, in combination with tamsulosin (see dutasteride/tamsulosin), under the brand names Combodart and Duodart.[55] It is also sold under a variety of generic brand names.[55] Dutasteride is also available in combination with alfuzosin under the brand names Alfusin-D and Dutalfa, but only in India.[55]

Availability

Dutasteride is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, many other European countries, Australia, and South Africa, as well as in Latin America, Asia, and elsewhere.[55] It is available as a generic medication in the United States and other countries.[52]

Research

Dutasteride has been studied in combination with bicalutamide in the treatment of prostate cancer.[56][57][58][59][60] 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.[34]

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Further reading
  • Frye, S. (2006). "Discovery and Clinical Development of Dutasteride, a Potent Dual 5α- Reductase Inhibitor". Current Topics in Medicinal Chemistry. 6 (5): 405–21. doi:10.2174/156802606776743101. PMID 16719800.
  • "Dutasteride". Drug Information Portal. U.S. National Library of Medicine.
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