The effect of other drugs on the pharmacokinetics Sildenafil Sildenafil metabolism occurs primarily in the liver under the influence of isoenzyme cytochrome CYP3A4 (major route) and CYP2C9, so inhibitors of these isozymes may reduce the clearance of sildenafil and inductors, respectively, to increase the clearance of sildenafil. A decrease in the clearance of sildenafil with simultaneous application of inhibitors of the cytochrome isoenzyme CYP3A4 (
ketoconazole,
erythromycin,
cimetidine).
Cimetidine (800 mg), a non-specific inhibitor of the cytochrome isoenzyme CYP3A4, when co-administered with sildenafil (50 mg) causes an increase in the concentration of sildenafil in plasma by 56%.
A single dose of 100 mg of sildenafil together with erythromycin (500 mg / day twice a day for 5 days), a specific inhibitor of the cytochrome CYP3A4 isoenzyme, with the achievement of a constant concentration of erythromycin in the blood, increases the sildenafil AUC by 182%.
With the simultaneous administration of sildenafil (once 100 mg) and saquinavir (1200 mg / day 3 times a day), the HIV protease inhibitor and the cytochrome CYP3A4 isoenzyme, while achieving a constant saquinavir concentration in the blood, Cmax sildenafil increased by 140%, and the AUC increased by 210%.
Sildenafil does not affect the pharmacokinetics of saquinavir. More potent cytochrome CYP3A4 isoenzyme inhibitors, such as
ketoconazole and
itraconazole, can cause and stronger changes in the pharmacokinetics of sildenafil. Simultaneous use of sildenafil (once 100 mg) and ritonavir (500 mg twice a day), an HIV protease inhibitor and a strong inhibitor of cytochrome P450, with the achievement of a constant concentration of ritonavir in the blood leads to an increase in Cmax sildenafil by 300% (4-fold ), and AUC - by 1000% (11 times).After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng / ml (after a single application of one sildenafil - 5 ng / ml).
Grapefruit juice, a weak inhibitor of CYP3A4, may moderately increase the plasma concentration of sildenafil.
If
sildenafil take in recommended doses of patients receiving simultaneously strong inhibitors of the cytochrome isoenzyme CYP3A4, then Cmax of free sildenafil does not exceed 200 nM, and the drug is well tolerated.
A single dose of antacid (hydroxide / magnesium hydroxide, aluminum) did not affect the bioavailability of sildenafil.
Inhibitors of the cytochrome isoenzyme CYP2C9 (such as tolbutamide,
warfarin), cytochrome CYP2D6 isoenzyme (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors (angiotensin converting enzyme), and calcium antagonists have no effect on the pharmacokinetic parameters of sildenafil.
Azithromycin (500 mg / day for 3 days) does not affect AUC, Cmax, Tmax, rate of elimination rate and T1 / 2 sildenafil or its main circulating metabolite.
Nicorandil is a hybrid of nitrate and potassium channel activator. Due to the presence of a nitrate component, it can enter into serious interactions with sildenafil. Effect of sildenafil on other drugs
Sildenafil is a weak inhibitor of cytochrome P450 - 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 isoenzymes (HKso> 150 μmol). When taking sildenafil in the recommended doses of it
Cmax is about 1 μmol, so it is unlikely that
sildenafil can affect the clearance of the substrates of these isoenzymes.
Sildenafil enhances the hypotensive effect of nitrates both with prolonged use of the latter, and when they are prescribed for acute indications. In this regard, the use of sildenafil in combination with nitrates or donators of nitric oxide is contraindicated.
With simultaneous administration of alpha-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional decrease in systolic / diastolic blood pressure in the supine position was 7/7 mm Hg. st., 9/5 mm Hg. Art. and 8/4 mm Hg. Art. respectively, while in the standing position it is 6/6 mm Hg.st., 11/4 mm Hg. Art. and 4/5 mm Hg. Art. respectively. We report rare cases of development in these patients of symptomatic postural hypotension, manifested as dizziness (without syncope). In individual sensitive patients receiving alpha-blockers, simultaneous use of sildenafil can lead to symptomatic hypotension. Signs of significant interaction of sildenafil (50 mg) with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the isoenzyme of cytochrome CYP2C9, have not been identified.
Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease, saquinavir and ritonavir inhibitors, which are substrates of the cytochrome CYP3A4 isoenzyme, at their constant level in the blood.
Sildenafil (50 mg) does not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg).
Sildenafil (50 mg) does not increase the hypotensive effect of ethanol in healthy volunteers with a maximum concentration of ethanol in the blood averaging 0.08% (80 mg / dL).
In patients with hypertension, there was no evidence of interaction between sildenafil (100 mg) and amlodipine.The average additional decrease in blood pressure in the prone position is 8 mm Hg. Art. (systolic) and 7 mm Hg. Art. (diastolic).
The use of sildenafil in combination with antihypertensive drugs does not lead to additional side effects.