Dutasia 0.5 Mechanism of Action

Pharmacology: Pharmacodynamics: Effect on 5a-Dihydrotestosterone and Testosterone: The maximum effect of daily doses of Dutasteride on the reduction of DHT is dose dependent and is observed within 1 to 2 weeks. After 1 and 2 weeks of daily dosing with Dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively.
Mechanism of Action: Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5a-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver.
Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5a-reductase isoenzymes, with which it forms a stable enzyme complex.
Pharmacokinetics: Absorption: Following administration of a single 0.5-mg dose of a tablet, time to peak serum concentrations (T_max) of Dutasteride occurs within 2 to 3 hours.
Absolute bioavailability in 5 healthy subjects is approximately 60% (range, 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10% to 15%. This reduction is of no clinical significance.
Distribution: Pharmacokinetic data following single and repeat oral doses show that Dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (96.6%).
Metabolism and Elimination: Dutasteride is extensively metabolized in humans. In vitro studies showed that Dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4'-hydroxy-dutasteride, 6-HYDROXYDUTASTERIDE, and the 6,4'-dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In human serum following dosing to steady state, unchanged Dutasteride, 3 major metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and 2 minor metabolites (6,4'-dihydroxydutasteride and 15-hydroxy-dutasteride), as assessed by mass spectrometric response, have been detected.
Dutasteride and its metabolites were excreted mainly in feces. As a percent of dose, there was approximately 5% unchanged Dutasteride (~1% to ~15%) and 40% as Dutasteride-related metabolites (~2% to ~90%). Only trace amounts of unchanged Dutasteride were found in urine (< 1%). Therefore, on average, the dose unaccounted for approximated 55% (range, 5% to 97%).