Dutasteride is an antiandrogenic compound that is used for the treatment of symptomatic benign prostatic hyperplasia (BPH) in adult males by inhibiting 5-alpha reductase.
Dutasteride is an oral synthetic 4-azasteroid. It is a novel dual 5α-reductase inhibitor that works by blocking both isoforms of 5α-reductase enzymes in a potent, selective, and irreversible manner.1 Type I and II 5α-reductase enzymes convert testosterone into dihydrotestosterone (DHT), a primary hormonal mediator that plays a role in the development and enlargement of the prostate gland. Dutasteride was approved by the FDA in 2001 for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men as monotherapy or in combination with the α-adrenergic antagonist TAMSULOSIN to enhance the therapeutic response.
Indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate gland to improve symptoms, and reduce the risk of acute urinary retention and the need for BPH-related surgery alone or in combination with TAMSULOSIN.
Dutasteride is a synthetic 4-azasteroid compound that selectively inhibits both the type I and type II isoforms of steroid 5α-reductase, an intracellular enzyme that converts testosterone to 5α-dihydrotestosterone (DHT). Dutasteride works by reducing the levels of circulating DHT. It was also shown to reduce the size of the prostate gland, improve urinary flow, and symptoms of benign prostatic hyperplasia alone or in combination with tamsulosin. The effect of the reduction of DHT by dutasteride is dose-dependent, with the maximum effect observed within 1-2 weeks following initial administration.
After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. The serum concentrations of DHT were maintained to be decreased by more than 90% in 85% of patients following 1 years’ administration of oral dutasteride 0.5 mg/day. As evident from the clinical studies, dutasteride may also cause decreases in serum PSA in the presence of prostate cancer.
The 5α-reductase is a nuclear-bound steroid intracellular enzyme primarily located in the prostatic stromal cell that converts the androgen testosterone into the more active metabolite, 5α-dihydrotestosterone (DHT). DHT is considered to be the primary androgen playing a role in the initial development and subsequent enlargement of the prostate gland. It serves as the hormonal mediator for the hyperplasia upon accumulation within the prostate gland. DHT displays a higher affinity towards androgen receptors in the prostate gland compared to testosterone and by acting on the androgen receptors, DHT modulates genes that are responsible for cell proliferation. Responsible for the synthesis of approximately one-third of circulating DHT, type I 5α-reductase is predominant in the sebaceous glands of most regions of skin, including the scalp, and liver. The type II 5a-reductase isozyme is primarily found in the prostate, seminal vesicles, epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT. Due to its dual inhibition of both isoenzymes of 5α-reductase, dutasteride causes a near-complete suppression of DHT.6 Compared to a 70% reduction of serum DHT levels caused by finasteride, a near-complete suppression of serum DHT-more than 90% is seen with dutasteride.
By forming a stable complex with both type I and type II 5α-reductase, dutasteride inhibits its enzymatic action of converting testosterone to 5α-dihydrotestosterone (DHT), which is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. It is proposed that DHT is the principal androgen responsible for prostatic growth in later life-normal masculinization of the external genitalia and maturation of the prostate gland during development-thus reducing the serum DHT levels results in reduced prostatic volume and increased epithelial apoptosis.11 Dutasteride is a competitive and specific inhibitor of both Type I and Type II 5α-reductase isoenzymes and when evaluated under in vitro and in vivo conditions, the dissociation of the drug from the drug-enzyme complex is reported to be extremely slow. Dutasteride does not bind to the human androgen receptor.
Following oral administration of a single dose of 0.5 mg dutasteride, the peak serum concentrations were reached within 2 to 3 hours. Following daily oral administration of 0.5 mg dutasteride, the steady-state concentration of 40 ng/mL is expected to be achieved at 6 months following initial administration. In healthy subjects, the absolute bioavailability was 60%, ranging from 40% to 94%. While food intake reduced the maximum serum concentrations by 10 to 15%, food intake is reported to have a negligible effect on the bioavailability of the drug.
Dutasteride displays a large volume of distribution ranging from 300 to 500 L. Following daily oral administration of 0.5 mg dutasteride healthy subjects for 12 months, the semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) with 11.5% of serum dutasteride concentrations being partitioned into semen.
Dutasteride is about 99% bound to albumin and 96.6% bound to α-1 acid glycoprotein in the serum.
Dutasteride undergoes extensive hepatic metabolism mediated by CYP3A4 and CYP3A5. 4′-hydroxydutasteride, 6-hydroxydutasteride, 6,4′-dihydroxydutasteride, 1,2-dihydrodutasteride, and 15-hydroxydutasteride metabolites are formed. 2 minor metabolites – 6,4′-dihydroxydutasteride and 15-hydroxydutasteride – can also be detected. According to in vitro studies, 4′-hydroxydutasteride and 1,2-dihydrodutasteride mediated inhibitory actions against both isoforms of 5α-reductase but with lower potency when compared to the parent drug. The activity of 6β-hydroxydutasteride is comparable to that of dutasteride.
Dutasteride and its metabolites mainly undergo fecal excretion. About 1-15% of the dose is excreted as the unchanged parent compound, while 2-90% of the total dose is excreted in the form of dutasteride-related metabolites in the feces. Trace amounts of unchanged dutasteride, with less than 1%, can also be detected in the urine. Therefore, on average, the dose unaccounted for approximated 55%, with a range between 5% and 97%.
The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. This long half-life accounts for the serum concentrations remaining detectable for up to 4 to 6 months after discontinuation of treatment.
Take with or without food. The absorption is unaffected by food.
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