Duoflow Mechanism of Action

Pharmacotherapeutic group: Alpha-adrenoreceptor antagonists. ATC-Code: G04CA52.
Pharmacology: Pharmacodynamics: Mechanism of action: DUOFLOW is a combination of two drugs with complementary mechanisms of action to improve symptoms in patients with BPH: dutasteride, a dual 5α-reductase inhibitor (5-ARI) and tamsulosin hydrochloride, an antagonist of α_1a-adrenoreceptors.
Dutasteride: Dutasteride inhibits the Type 1 and 2 5α-reductase isoenzymes which are responsible for the conversion of testosterone to 5α-dihydrotestosterone (DHT) and therefore causes a fall in the DHT level in the circulation and in the prostate. DHT is the main androgen responsible for hyperplasia of the glandular prostate tissue.
Dutasteride reduces the size of the prostate, relieves the symptoms, improves urine flow and reduces the risk of acute urinary retention and the need for surgery.
Tamsulosin: Tamsulosin is a selective α1-adrenoreceptor blocker for the symptomatic treatment of functional symptoms of benign prostatic hyperplasia. It binds selectively and competitively to postsynaptic α1-adrenoreceptors (mainly the alpha_1a subtype - approximately 75% of the α1-receptors in the prostate are of the α_1a subtype) responsible for contraction of the smooth muscle of the prostate and urethra. Tamsulosin thereby reduces smooth muscle tension in the prostate and urethra. This increases maximum urinary flow rate and reduces urinary tract obstruction. It also improves the complex of irritative and obstructive symptoms in which bladder instability and tension of the smooth muscles of the lower urinary tract play an important role.
Effects on DHT/testosterone: The peak effect of dutasteride in the sense of reduction of DHT is dose-dependent and occurs within 1-2 weeks. After taking dutasteride (0.5 mg/day) for one or two weeks, the mean DHT concentrations in the serum were reduced by 85% and 90% respectively, after one year by 94% and after 2 years by 93%. After discontinuation of treatment the DHT serum concentrations associated with the clinical effects return to the baseline values within about 4 months.
The mean rise in the serum testosterone level was 19% after both one and two years. The testosterone concentrations fluctuated within the normal physiological range.
Safety Pharmacodynamics: Adrenergic alpha-1 receptor blockers can reduce blood pressure by lowering peripheral resistance.
Pharmacokinetics: Absorption: Dutasteride: After oral administration the peak serum concentration of dutasteride is attained within 1-3 hours. Absolute bioavailability compared with a 2-hour intravenous infusion is approx. 60%.
Tamsulosin: Tamsulosin hydrochloride is absorbed from the intestine and is almost completely available. After a single dose following a meal, tamsulosin plasma concentrations reach their peak after 6 hours.
Tamsulosin hydrochloride has linear absorption kinetics, with achievement of steady state concentrations by about the fifth day of once-a-day dosing. The rate of absorption of tamsulosin hydrochloride is reduced by a recent meal. Uniformity of absorption can be promoted by the patient always taking tamsulosin hydrochloride 30 minutes after the same meal each day.
Tamsulosin plasma levels exhibit considerable inter-individual variability with both single and multiple dosing.
Distribution: Dutasteride: Dutasteride has a large volume of distribution (300-500 l) and is highly plasma protein bound (>99.5%; to albumin and alpha-1 acid glycoprotein). The steady-state serum concentration (C_ss) of approx. 40 ng/ml at a dose of 0.5 mg dutasteride a day is achieved after 6 months. After 1 and 3 months the dutasteride serum levels reach 65% and about 90% respectively of the steady-state concentration. The steady-state concentration is also reached in seminal fluid after 6 months.
After administration for 12 months the dutasteride concentration in seminal fluid was on average 3.4 ng/ml (range 0.4-14 ng/ml), i.e., on average 11.5% of the serum level.
Tamsulosin: The volume of distribution of tamsulosin hydrochloride is low (approx. 0.2 l/kg). Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha-1 acid glycoprotein (AAG).
Metabolism: Dutasteride: Dutasteride undergoes extensive metabolism. It is mainly hydroxylated and dehydrogenated to inactive metabolites. There are 4 major metabolites and 6 subsidiary metabolites. Hydroxylation takes place in vitro via CYP3A4.
Tamsulosin: Tamsulosin hydrochloride is extensively metabolised slowly by cytochrome P450 enzymes in the liver. In vitro results indicate that CYP3A4 and CYP2D6, and to a minor extent some other CYP isoenzymes, are involved in the metabolism of tamsulosin. However, the majority is present in the plasma in the form of the unchanged active ingredient. None of the metabolites is more active or more toxic than the parent substance. The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulphate prior to renal excretion.
Elimination: Dutasteride: 5.4% of the dose administered is excreted as unchanged dutasteride in the faeces, and the rest in the form of metabolites. Only traces of the unchanged substance (less than 0.1% of the dose) can be detected in the urine.
Dutasteride clearance is low. The elimination half-life is 3-5 weeks.
Tamsulosin: Following oral administration of tamsulosin in the form of modified release capsules, the apparent elimination half-life in the fed state after a single dose is approximately 10 hours and in the steady state is approximately 13 hours. Approximately 10% of the substance is excreted unchanged in urine.
Kinetics of special patient populations: No pharmacokinetic studies have been conducted with DUOFLOW on special patient populations. The following statements reflect the information available on the individual components.
Elderly: Dutasteride: In the age groups >50-65 years and >70 years there were no statistically significant differences in pharmacokinetics.
Tamsulosin: Findings indicate that overall exposure is approx. 40% increased in patients aged 55-75 years compared with young males.
Renal impairment: Dutasteride: The effects of renal impairment on the pharmacokinetics of dutasteride have not been investigated. As less than 0.1% of the dose is excreted in the urine, no effect on the serum levels is to be expected.
Tamsulosin: No clinically relevant changes in the pharmacokinetics of tamsulosin were observed in patients with mild to moderate (30≤CLcr <70 mL/min/1.73m²) or moderate to severe (10≤CLcr <30 mL/min/1.73m²) renal impairment compared with subjects with normal renal function. However, patients with terminal renal disease (CLcr <10 mL/min/1.73m²) have not been studied.
Hepatic impairment: Dutasteride: The effects of hepatic impairment on the pharmacokinetics of dutasteride have not been investigated.
Tamsulosin: In patients with mild to moderate hepatic dysfunction (Child-Pugh classification: Grades A and B), no clinically relevant changes in the pharmacokinetics of tamsulosin hydrochloride were observed. Tamsulosin hydrochloride has not been studied in patients with severe hepatic dysfunction (Child-Pugh C).
Toxicology: Preclinical safety data: Not applicable.