A 5-Alpha reductase inhibitor.
Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of an enlarged prostate.
It is a 5α-reductase inhibitor, which blocks the action of the 5α-reductase enzymes that convert testosterone into DHT.
It is a competitive, irreversible inhibitor of all three isoforms of 5α-reductase, types I, II, and III.
It may take a few months before benefits occur.
It is also used for scalp hair loss in men and as a part of hormone therapy in transgender women.
It is taken orally.
Pregnancycategory-Not to be used during pregnancy.
Exposure during pregnancy is contraindicated because dutasteride, being a form of antiandrogen, may interfere with the sexual differentiation of the male fotus.
5α-Reductase inhibitor- drug class
Bioavailability 60%.
Protein binding 99%.
Metabolism
Liver (CYP3A4)
Metabolites
4′-Hydroxydutasteride
6′-Hydroxydutasteride
1,2-Dihydrodutasteride
Elimination half-life 4–5 weeks
Excretion
Feces: 40% as metabolites
Urine: 5%
Inhibits the conversion of testosterone to 5 alpha-dihydrotestosterone (DHT), which is the androgen mainly responsible for development and enlargement of the prostate.
It is used for treating benign prostatic hyperplasia (BPH).
Dutasteride of Prostate Cancer Events (REDUCE) trial including 7000 men, and reduced prostate cancer incidence by 23% after 4 years of treatment.
It has a 25–26% reduction in the risk of developing prostate cancer with 5α-reductase inhibitor chemoprevention, but may increase the risk of developing certain rare but aggressive forms of prostate cancer.
There is insufficient data to determine if they have an effect on the overall risk of death from prostate cancer.
Dutasteride inhibits all three 5α-reductase isoenzymes and can decrease DHT levels by 95%.
It can also reduce DHT levels in the prostate by 97 to 99% in men with prostate cancer.
It is a beneficial adjunct to men with low risk prostate cancer, significantly reducing the risk of progression by 38%.
Dutasteride is approved for the treatment of male androgenetic alopecia in some foreign countries.
It induces hair regrowth in men more rapidly and to a greater extent than even the highest approved dosage of finasteride.
The superior effectiveness of dutasteride relative to finasteride for male pattern hair loss is related to the fact that the inhibition of 5α-reductase and consequent reduction of DHT production within the hair follicles is more complete with dutasteride.
It is also used off-label in the treatment of female pattern hair loss.
5α-reductase inhibitors like finasteride have been found to be effective in the treatment of hirsutism in women.
Dutasteride may be more effective than finasteride for hirsutism in women due to the fact that its inhibition of the 5α-reductase enzyme is comparatively more complete.
Dutasteride is sometimes used as a component of hormone therapy for transgender women in combination with an estrogen and/or another antiandrogen like spironolactone.
Dutasteride is provided in the form of soft oil-filled gelatin oral capsules containing 0.5 mg dutasteride each.
Contraindications:
Women who are or who may become pregnant should not handle the drug: can cause birth defects, specifically ambiguous genitalia and undermasculinization, in male fetuses due to its antiandrogenic effects and is seen naturally in 5α-reductase deficiency.
Women who are pregnant should never take dutasteride.
People taking dutasteride should not donate blood to prevent birth defects if a pregnant woman 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.
Dutasteride produces minimal side effects.
Adverse effects include: headache and gastrointestinal discomfort, menstrual changes, acne, and dizziness, a small risk of gynecomastia in men.
The risk of gynecomastia with 5α-reductase inhibitors is about 2.8%.
The increased risk of high-grade prostate cancer, has been suggested but is probably overstated.
It may temporarily reduce the growth and prevalence of benign prostate tumors, but could also mask the early detection of prostate cancer.
Sexual dysfunction, such as erectile dysfunction, loss of libido, or reduced semen volume are side effects of 5α-reductase inhibitors, occurring in as many as 4.8% of all patients, which in some cases may persist after discontinuing medication, leading to a lower quality of life.
Several small studies have reported an association between 5α-reductase inhibitors and depression.
Dutasteride is not lethal despite taking 100 times the normal dose.
It is thought that 5α-reductase inhibitors like dutasteride may prevent the formation of neurosteroid metabolites like allopregnanolone from progesterone and hence may mitigate the psycho-cognitive effects of progesterone.
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.
5α-reductase inhibitors did not result in a consistent increase in testosterone levels, with some studies showing increases and others showing no change; there is no statistically significant change in testosterone levels from 5α-reductase inhibitors in the overall meta-analysis.
5α-reductase inhibitors like dutasteride are neurosteroidogenesis inhibitors, preventing the 5α-reductase-mediated biosynthesis of various neurosteroids.
These neurosteroids are potent positive allosteric modulators of the GABAA receptor and have been found to possess antidepressant, anxiolytic, and pro-sexual effects.
Prevention of neurosteroid formation may be involved in the sexual dysfunction and depression that has been associated with 5α-reductase inhibitors like dutasteride.
The oral bioavailability of dutasteride is approximately 60%.
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, which are active 5α-reductase inhibitors.
Dutasteride has an 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 dutasteride requires 5 or 6 months to reach steady state concentrations.
No dosage adjustment is necessary in the elderly nor in renal impairment.
It also remains in the body for a long time, and can be detected for up to 4 to 6 months after discontinuation.
Dutasteride is eliminated mainly in the feces (40%) as metabolites, and )5%) is eliminated unchanged in the urine.
It is an analogue of finasteride.
Dutasteride has been studied in combination with bicalutamide in the treatment of prostate cancer.
It blocks the formation of the neurosteroid allopregnanolone from progesterone, is effective in reducing symptoms in women with premenstrual dysphoric disorder.