Dutasteride-antiandrogen drug and its pharmacology

DESCRIPTION:

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 also belongs to this group, but while dutasteride inhibits both isoforms of 5-alpha reductase, finasteride inhibits only one. Even so, a clinical study done by GlaxoSmithKline, the EPICS trial, did not find dutasteride to be more effective than finasteride in treating BPH. 

PHARMACOKINETICS : 

 Absorption:Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak serum concentrations (Tmax) 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%

Distritbution: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 metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4'-hydroxydutasteride, 6-hydroxydutasteride, and the 6,4'-dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. 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 dutasteoride were found in urine ( < 1%). Therefore, on average, the dose unaccounted for approximated 55% (range: 5% to 97%).

 Volume of distribution: 300 to 500 L

 Protein binding: Highly bound to albumin (99%) and a-1 acid glycoprotein (96.6%).

 Half life: 5 weeks

PHARMACODYNAMICS:

 Dutasteride is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5 alpha-reductase (5AR), intracellular enzymes that convert testosterone to 5 alpha-dihydrotestosterone (DHT). Type I 5a-reductase is predominant in the sebaceous glands of most regions of skin, including scalp, and liver. Type I 5a-reductase is responsible for approximately one-third of circulating DHT. The Type II 5a-reductase isozyme is primarily found in prostate, seminal vesicles, epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT.

SIDE EFFECTS: 

 Inability to have or maintain an erection , decrease in sex drive , problems with ejaculation , swelling of the face, tongue, or throat , difficulty breathing or swallowing , peeling skin and may increase the risk of high grade prodtrate cancer.

DRUG-DRUG INTERACTION:

 1. Dutasteride + Ketokonazole = The serum concentration of Dutasteride can be increased.

 2. Dutasteride + Virapamil,diltizam(calcium channel blocker) = Decrease in clearance of dutasteride.

 3. Dutasteride + Cobisiscat = The serum concentration of Dutasteride can be increased.

CONTRAINDICATIONS:

 1. Should not be given to children and pregnant women. Rapidly absorded from dkin, if come in contact then washed with soapy water.

 2. Person taking this medicatin should not donate blood.

THERAPEUTIC USES: 

1. Benign prostatic hyperplasia (BPH).

REFERENCE:-Tripathi K D"Essential of medical pharmacology",7th edition ,page no-303,858.