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Dutasteride

Clinical data
Trade names	Avodart, others; Combodart, Duodart (with tamsulosin)
Other names	GG-745; GI-198745; GI-198745X; N--3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide
AHFS/Drugs.com	Monograph
MedlinePlus	a603001
Pregnancy category	Not to be used during pregnancy
Routes of administration	By mouth
Drug class	5α-Reductase inhibitor
ATC code	G04CB02 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	60%
Protein binding	99%
Metabolism	Liver (CYP3A4)
Metabolites	• 4'-Hydroxydutasteride • 6'-Hydroxydutasteride • 1,2-Dihydrodutasteride (All three active)
Elimination half-life	4–5 weeks
Excretion	Feces: 40% (metabolites) Urine: 5% (unchanged)
Identifiers
IUPAC name (1S,3aS,3bS,5aR,9aR,9bS,11aS)-N--9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindenoquinoline-1-carboxamide
CAS Number	164656-23-9
PubChem CID	6918296
IUPHAR/BPS	7457
DrugBank	DB01126
ChemSpider	5293502
UNII	O0J6XJN02I
KEGG	D03820
ChEBI	CHEBI:521033
ChEMBL	ChEMBL1200969
CompTox Dashboard (EPA)	DTXSID8046452
ECHA InfoCard	100.166.372
Chemical and physical data
Formula	C27H30F6N2O2
Molar mass	528.539 g·mol
3D model (JSmol)	Interactive image
SMILES FC(F)(F)c1cc(c(cc1)C(F)(F)F)NC(=O)32(CC4(2CC3)CC5NC(=O)\C=C/45C)C
InChI InChI=1S/C27H30F6N2O2/c1-24-11-9-17-15(4-8-21-25(17,2)12-10-22(36)35-21)16(24)6-7-19(24)23(37)34-20-13-14(26(28,29)30)3-5-18(20)27(31,32)33/h3,5,10,12-13,15-17,19,21H,4,6-9,11H2,1-2H3,(H,34,37)(H,35,36)/t15-,16-,17-,19+,21+,24-,25+/m0/s1 Key:JWJOTENAMICLJG-QWBYCMEYSA-N
(verify)

Dutasteride, sold under the brand name Avodart among others, is a medication used primarily to treat enlarged prostate in men. It can also be used to treat scalp hair loss in men, excessive hair growth in women, and as a part of hormone therapy for transgender women. It is taken by mouth.

Dutasteride is a 5α-reductase inhibitor, and hence is a type of antiandrogen. Dutasteride works by decreasing the production of dihydrotestosterone (DHT), an androgen sex hormone, in certain parts of the body like the prostate gland and the scalp. It inhibits all three forms of 5α-reductase, and can decrease DHT levels in the blood by up to 98%. The FDA has warned that the drug increases the risk of certain rare forms of prostate cancer, and that some men may experience sexual dysfunction, depression, anxiety, or breast enlargement. Side effects are generally mild.

Dutasteride was developed by GlaxoSmithKline. It was patented in 1996 and introduced for the treatment of enlarged prostate in 2001. The drug has been approved for the treatment of scalp hair loss in South Korea since 2009 and in Japan since 2015. It has not been approved for this indication in the United States, though it is often used off-label. The drug is available as a generic medication.

Medical uses

Enlarged prostate

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

Prostate cancer

A 2010 Cochrane review found a 25–26% reduction in the risk of developing prostate cancer with 5α-reductase inhibitor chemoprevention. 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. There is insufficient data to determine if they have an effect on the overall risk of death from prostate cancer.

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. 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. 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. Dutasteride has also been used off-label in the treatment of female pattern hair loss.

Excessive hair growth

Although no reports specific to dutasteride currently exist, 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. 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. Other studies using finasteride for hirsutism have also found it to be clearly effective. 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.

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. It may be useful for treating scalp hair loss or in those who cannot tolerate spironolactone.

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. This is due to its antiandrogenic effects and is seen naturally in 5α-reductase deficiency. As such, women who are pregnant should never take dutasteride. 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.

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

Adverse effects

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

The FDA has added a warning to dutasteride about an increased risk of high-grade prostate cancer. 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.

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. This is linked to lower quality of life and can cause stress in relationships. It has been reported that in a subset of men, these adverse sexual side effects may persist even after discontinuation of finasteride or dutasteride. Some have decreased sperm numbers as low as 10% of pretreatment values.

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

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).

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. It is a competitive, mechanism-based (irreversible) inhibitor of all three isoforms of 5α-reductase, types I, II, and III (IC₅₀Tooltip Half-maximal inhibitory concentration values are 3.9 µM for type I and 1.8 µM for type II). This is in contrast to finasteride, which is similarly an irreversible inhibitor of 5α-reductase but only inhibits the type II and III isoenzymes. 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%. 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, where the type II isoform of 5α-reductase predominates.

Since 5α-reductase inhibitors 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. 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 have a higher chance of having experiencing 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), THDOCTooltip tetrahydrodeoxycorticosterone (from deoxycorticosterone), and 3α-androstanediol (from testosterone). These neurosteroids are potent positive allosteric modulators of the GABA_A receptor and have been found to possess antidepressant, anxiolytic, and pro-sexual effects in animal research. 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.

Pharmacokinetics

The oral bioavailability of dutasteride is approximately 60%. Food does not adversely affect the absorption of dutasteride. Peak plasma levels occur 2 to 3 hours after administration. Levels of dutasteride in semen have been found to be 3 ng/mL, with no significant effects on DHT levels in sexual partners. The drug is extensively metabolized in the liver by CYP3A4. 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. All three metabolites are active; 6'-hydroxydutasteride has similar potency as a 5α-reductase inhibitor to dutasteride, while the other two are less potent. Dutasteride has an extremely long terminal or elimination half-life of about 4 or 5 weeks. 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). No dosage adjustment is necessary in the elderly nor in renal impairment. 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. In contrast to dutasteride, finasteride has a short terminal half-life of only 5 to 8 hours. Dutasteride is eliminated mainly in the feces (40%) as metabolites. A small portion (5%) is eliminated unchanged in the urine.

Chemistry

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

History

Dutasteride was patented in 1996 and was first described in the scientific literature in 1997. 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. Dutasteride has subsequently been introduced in many other countries, including throughout Europe and South America. 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.

Society and culture

Generic names

Dutasteride is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name.

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. It is also sold under a variety of generic brand names. Dutasteride is also available in combination with alfuzosin under the brand names Alfusin-D and Dutalfa, but only in India.

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. It is available as a generic medication in the United States and other countries.

Research

Dutasteride has been studied in combination with bicalutamide in the treatment of prostate cancer. 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.

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External links

• Avodart full prescribing information
• 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.

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