Dutasteride

Dutasteride

Systematic (IUPAC) name
(5α, 17β)-N-{2,5 bis(trifluoromethyl) phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide
Clinical data
Trade names	Avodart
AHFS/Drugs.com	monograph
MedlinePlus	a603001
Pregnancy cat.	X(US) Not to be handled by pregnant women
Legal status	POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	60%
Protein binding	99%
Metabolism	Hepatic (CYP3A4-mediated)
Half-life	5 weeks
Excretion	Fecal
Identifiers
CAS number	164656-23-9
ATC code	G04CB02
PubChem	CID 6918296
DrugBank	APRD00385
ChemSpider	5293502 Y
UNII	O0J6XJN02I Y
KEGG	D03820 N
ChEBI	CHEBI:521033 N
ChEMBL	CHEMBL1200969 N
Chemical data
Formula	C27H30F6N2O2
Mol. mass	528.53 g/mol
SMILES	eMolecules & PubChem
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 Y Key:JWJOTENAMICLJG-QWBYCMEYSA-N Y
NY(what is this?)  (verify)

Dutasteride (trade name Avodart by GlaxoSmithKline) is a dual 5-a reductase inhibitor that inhibits conversion of testosterone to dihydrotestosterone (DHT).

Dutasteride is FDA approved for treatment of benign prostatic hyperplasia (BPH) and is also prescribed off-label for treatment of male pattern baldness (MPB).

Medical uses

Phase I and II clinical trials for dutasteride as a hair loss drug were undertaken, but called off in late 2002, with reasons for terminatation unknown.

The phase II results indicated that dutasteride at both 0.5 mg and 2.5 mg/day generated a superior hair count to finasteride 5 mg at 12 and 24 weeks.

Phase II study results at 24 weeks:

• Placebo: - 32.3 hairs

• Finasteride 5 mg: + 75.6 hairs

• Dutasteride 0.1 mg: + 78.5 hairs

• Dutasteride 0.5 mg: + 94.6 hairs

• Dutasteride 2.5 mg: + 109.6 hairs

In December 2006, GlaxoSmithKline launched a new phase III, six month study in Korea to test the safety, tolerability and effectiveness of a once-daily dose of dutasteride (0.5 mg) for the treatment of MPB in the vertex region of the scalp (types IIIV, IV and V on the Hamilton-Norwood scale). The study was completed in January 2009. Future intentions by GlaxoSmithKline to continue or abandon plans for FDA approval of dutasteride in treatment of male pattern baldness (MPB) remain unknown.

Contraindications

The teratogenic effect (abnormalities of physiological development) from dutasteride is harmful to male children. Women who are pregnant should not handle the capsules, as inadvertent consumption, such as skin contact, could cause birth defects of the male fetus. The adverse effects would be similar to 5-alpha-reductase deficiency, where a developing male child is naturally deficient in 5-alpha reductase type II, and thus unable to synthesize it. As dutasteride blocks the same process, developing males would have a DHT deficiency with its adverse effects as a result of the drug. Men who are 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. These precautions are to be taken in order to prevent the potential risk of causing birth defects in a pregnant woman who receives a transfusion with blood that contains dutasteride.

Adverse effects

Clinical trial results

Month 0-6 ( n = 2,167 )

• Impotence: 4.7%
• Decreased libido: 3%
• Ejaculation disorders: 1.4%
• Breast disorders: 0.5%

Month 7-12 ( n = 1,901 )

• Impotence: 1.4%
• Decreased libido: 0.3%
• Ejaculation disorders: 0.5%
• Breast disorders: 1.1%

Month 13-18 ( n = 1,725 )

• Impotence: 1%
• Decreased libido: 0.1%
• Ejaculation disorders: 0.4%
• Breast disorders: 0.8%

Month 19-24 ( n = 1,605 )

• Impotence: 0.8%
• Decreased libido: 0.3%
• Ejaculation disorders: 0.1%
• Breast disorders: 0.6%

Observed in practice

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

Mechanism of action

Dutasteride belongs to a class of drugs called 5-alpha-reductase inhibitors, which block the action of the 5-alpha-reductase enzymes that convert testosterone into dihydrotestosterone (DHT). Finasteride, which is also approved for the treatment of benign prostatic hyperplasia (BPH), in addition to the treatment of male pattern baldness (MPB), belongs to this class of drugs. Dutasteride inhibits both isoforms of 5-alpha reductase, type I and type II, whereas finasteride only inhibits type II. There are no long-term randomized trials comparing the effects of dutasteride and finasteride in patients with BPH. The EPICS trial, a 12-month clinical study done by GlaxoSmithKline, demonstrated treatment with dutasteride and finasteride resulted in similar decreases in prostate volume, with numerically but not statistically significantly greater improvements in symptom scores for the dutasteride group. Finasteride is marketed by Merck under trademark names Proscar (5 mg/day finasteride) for BPH and Propecia (1 mg/day finasteride) for MPB. Published data from controlled clinical trials demonstrated the 5 mg dose of finasteride did not produce better results than the 1 mg dose.

Chemical synthesis

Avodart (dutasteride) 500 µg soft capsules (AU)

Batchelor, K. W.; Frye, S. V.; Dorsey, G. F.; Mook, R. A.; 1996, U.S. Patent 5,565,467.

See also

• Finasteride, related 5-alpha reductase inhibitor.

External links

• Avodart | Official website