Selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5). Crystalline solid. It is practically insoluble in water, very slightly soluble in ethanol. The molecular weight of 389.41.
Pharmacological action – improves erectile function. An erection during sexual stimulation is caused by an increase in blood flow to the tissues of the penis due to relaxation of the smooth muscles of arteries and cavernous bodies.
This process is mediated by the release of nitric oxide from the nerve endings and endothelial cells of the corpus cavernosum. Nitric oxide stimulates cGMP synthesis in smooth muscle cells. The accumulation of cGMP leads to muscle relaxation and an increase in blood flow to the corpora cavernosa. Inhibition of PDE5 by tadalafil is accompanied by an increase in the amount of cGMP and increased erectile function. Since sexual stimulation is necessary to initiate the local release of nitric oxide, inhibition of PDE5 by tadalafil in the absence of stimulation is not effective.
In vitro studies have shown that tadalafil is a selective PDE5 inhibitor. PDE5 was found in the smooth muscles of the corpora cavernosa, in the smooth muscles of blood vessels and internal organs, in skeletal muscles, platelets, kidneys, lungs, cerebellum and pancreas.
In vitro studies have shown that the effect of tadalafil on PDE5 is stronger than on other phosphodiesterases. So, tadalafil is 10,000 times more powerful against PDE5 than with PDE1, PDE2, PDE4 and PDE7, which are localized in the heart, brain, blood vessels, liver, white blood cells, skeletal muscles and other organs. The activity of tadalafil in relation to PDE5 is more than 10,000 times higher than that in relation to PDE3, an enzyme found in the heart and blood vessels. In addition, tadalafil is 700 times more active against PDE5 than with PDE6, which is found in the retina and is responsible for color perception. Tadalafil is 9000 times more potent (see also https://cialisguru.com/buy-tadalafil-10-mg/) for PDE5 than PDE8, PDE9 and PDE10 and 14 times more potent for PDE5 than PDE11A1, an enzyme found in skeletal muscle. Tadalafil inhibits the activity of human recombinant PDE11A1 at concentrations within the therapeutic range. The physiological role and clinical significance of PDE11 inhibition in humans have not been determined.
Tadalafil is rapidly absorbed by ingestion. After ingestion of a single dose, Tmax is from 30 minutes to 6 hours (on average 2 hours), the absolute bioavailability has not been determined. The rate and extent of absorption are independent of food intake.
The average apparent volume of distribution after ingestion is approximately 63 L, which indicates that tadalafil is distributed in the tissues. At therapeutic concentrations, 94% of tadalafil is associated with plasma proteins.
In healthy volunteers, less than 0.0005% of the dose taken was found in semen. In healthy volunteers, the AUC of tadalafil increases in proportion to the dose in the dose range of 2.5–20 mg. The equilibrium concentration is achieved within 5 days with a daily intake of 1 time per day, while the AUC is approximately 1.6 times greater than when taking a single dose.
Tadalafil is metabolized predominantly with the participation of CYP3A4 to catechol, which undergoes methylation and glucuronidation to form methylcatechol and a conjugate of methylcatechol with glucuronide, respectively. The main circulating metabolite is methylcatecholglucuronide, the concentration of methylcatechol is less than 10% of that for glucuronide. In vitro data indicate that metabolites at the observed concentrations do not have pharmacological activity.
Oral clearance of tadalafil – 2.5 l / h, terminal T1 / 2 – 17.5 hours in healthy volunteers. Tadalafil is excreted mainly in the form of metabolites, mainly with feces (approximately 61% of the dose taken) and to a lesser extent with urine (approximately 36%).