Tamzor Duo Mechanism of Action

Pharmacotherapeutic group: Urologicals, Alpha-adrenoreceptor antagonists. ATC Code: G04CA52.
Pharmacology: Dutasteride/Tamsulosin is a combination of two drugs: Dutasteride, a dual 5α-reductase inhibitor (5 ARI) and Tamsulosin hydrochloride, an antagonist of α1a and α1d adrenoreceptors. These drugs have complementary mechanisms of action that rapidly improve symptoms, urinary flow and reduce the risk of acute urinary retention (AUR) and the need for BPH related surgery.
Dutasteride: Dutasteride inhibits the conversion of testosterone to 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 5α-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 5-α-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.
Tamsulosin: Smooth muscle tone is mediated by the sympathetic nervous stimulation of α1-adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH.
Tamsulosin, an α1-adrenoceptor blocking agent, exhibits selectivity for α1-receptors in the human prostate. At least 3 discrete α1-adrenoceptor subtypes have been identified: α1A, α1B, and α1D; their distribution differs between human organs and tissue. Approximately 70% of the α1-receptors in human prostate are of the α1a subtype. Tamsulosin is not intended for use as an antihypertensive.
Pharmacokinetics: The pharmacokinetics of Dutasteride and Tamsulosin from Dutasteride and Tamsulosin hydrochloride capsules are comparable to the pharmacokinetics of Dutasteride and Tamsulosin when administered separately.
Absorption: The pharmacokinetic parameters of Dutasteride and Tamsulosin observed after administration of Dutasteride and Tamsulosin hydrochloride capsules in a single-dose, randomized, 3-period, partial cross-over trial.
Dutasteride: Following administration of a single 0.5 mg dose of a soft gelatin capsule, time to peak absolute bioavailability in 5 healthy subjects is approximately 60% (range: 40% to 94%).
Tamsulosin: Absorption of Tamsulosin is essentially complete (>90%) following oral administration of 0.4 mg Tamsulosin hydrochloride capsules under fasting conditions. Tamsulosin exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-daily dosing.
Distribution: Dutasteride: 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%) and α-1-acid glycoprotein (AAG, 96.6%).
Tamsulosin: The mean steady-state apparent volume of distribution of Tamsulosin after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body. Tamsulosin is extensively bound to human plasma proteins (94% to 99%), primarily AAG, with linear binding over a wide concentration range (20-600 ng/mL).
Metabolism: Dutasteride: Dutasteride is extensively metabolized in humans. In vitro, Dutasteride is metabolised by the cytochrome P450 3A4 and 3A5 to three monohydroxylated metabolites and one dihydroxylated metabolite. Following oral dosing of Dutasteride 0.5 mg/day to steady state, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as unchanged Dutasteride in the faeces. The remainder is excreted in the faeces as 4 major metabolites comprising 39%, 21%, 7%, and 7% each of drug-related material and 6 minor metabolites (less than 5% each). Only trace amounts of unchanged Dutasteride (less than 0.1% of the dose) are detected in human urine.
Tamsulosin: There is no enantiomeric bioconversion from Tamsulosin [R(-)isomer] to the S(+) isomer in humans. Tamsulosin is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. In vitro studies indicate that CYP3A4 and CYP2D6 are involved in metabolism of Tamsulosin as well as some minor participation of other CVP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to Tamsulosin. The metabolites of Tamsulosin undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.
Excretion: Dutasteride: The elimination of Dutasteride is dose dependent and the process appears to be described by two elimination pathways in parallel, one that is saturable at clinically relevant concentrations and one that is non saturable. At low serum concentration (less than 3 ng/mL), Dutasteride is cleared rapidly by both the concentration dependent and concentration independent elimination pathways. Single doses of 5 mg or less showed evidence of rapid clearance and a short half-life of 3 to 9 days.
At therapeutic concentrations, following repeat dosing of 0.5 mg/day, the slower, linear elimination pathway is dominating and the half-life is approximately 3-5 weeks.
Tamsulosin: Tamsulosin and its metabolites are mainly excreted in the urine with about 9% of a dose being present in the form of unchanged active substance. Following intravenous or oral administration of an immediate-release formulation, the elimination half life of Tamsulosin in plasma ranges from 5 to 7 hours. Due to the absorption rate-controlled pharmacokinetics with Tamsulosin modified release capsules, the apparent elimination half life of Tamsulosin in the fed state is approximately 10 hours and in the steady state is approximately 13 hours.