The effect of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil (the pharmacokinetics of sildenafil) occurs mainly under the action of the isoenzyme CYP3A4 (the main pathway), so inhibitors of this isoenzyme can reduce the clearance of sildenafil, and inducers, respectively, increase the clearance of sildenafil. There was a decrease in the clearance of sildenafil with the simultaneous use of inhibitors of the CYP3A4 isoenzyme (ketoconazole, erythromycin, cimetidine).

Cimetidine (800 mg), a non-specific inhibitor of the CYP3A4 isoenzyme, when taken together 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 2 times a day for 5 days), a moderate inhibitor of the CYP3A4 isoenzyme, against the background of achieving a constant concentration of erythromycin in the blood, leads to an increase in the AUC of sildenafil by 182%.

When taking sildenafil (once 100 mg) and saquinavir (1200 mg/day 3 times a day), an HIV protease inhibitor and CYP3A4 isoenzyme, against the background of achieving a constant concentration of saquinavir in the blood, the Cmax of sildenafil increased by 140%, and the AUC increased by 210%.

Stronger inhibitors of the CYP3A4 isoenzyme, such as ketoconazole and itraconazole, can also cause more pronounced changes in the pharmacokinetics of sildenafil.

Simultaneous use of sildenafil (once 100 mg) and ritonavir (500 mg 2 times a day), an HIV protease inhibitor and a strong cytochrome P450 inhibitor, against the background of achieving a constant concentration of ritonavir in the blood leads to an increase in the Cmax of sildenafil by 300% (4 times), 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). This is consistent with the effect of ritonavir on a wide range of cytochrome P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Taking into account these data, simultaneous administration of ritonavir and sildenafil is not recommended. In any case, the maximum dose of sildenafil under no circumstances should exceed 25 mg for 48 hours. If sildenafil is taken in the recommended doses by patients receiving strong inhibitors of the CYP3A4 isoenzyme at the same time, then the cmax of free sildenafil does not exceed 200 nM, and the drug is well tolerated.

A single dose of antacid (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.

In studies involving healthy volunteers, with the simultaneous use of an endothelin receptor antagonist, bosentan (an inducer of the CYP3A4 isoenzyme (moderate), CYP2C9 and possibly CYP2C19) in Css (125 mg 2 times a day) and sildenafil in Css (80 mg 3 times a day), there was a decrease in the AUC and Cmax of sildenafil by 62.6 and 52.4%, respectively. Sildenafil increased the AUC and Cmax of bosentan by 49.8 and 42%, respectively.

It is assumed that the simultaneous use of sildenafil with powerful inducers of the CYP3A4 isoenzyme, such as rifampicin, may lead to a greater decrease in the concentration of sildenafil in blood plasma.

Inhibitors of the CYP2D6 isoenzyme (SSRIs, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists do not affect the pharmacokinetics of sildenafil.

Pharmacokinetics of sildenafil

The effect of sildenafil on other drugs

Sildenafil enhances the hypotensive effect of nitrates both with prolonged use of the latter, and when they are prescribed for urgent indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated. With simultaneous administration of the alpha-adrenoblocker doxazosin (4 and 8 mg) and sildenafil (25, 50 and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional decrease in sAD/dAD in the supine position was 7/7, 9/5 and 8/4 mm Hg, respectively, and in the standing position-6/6, 11/4 and 4/5 mm Hg. accordingly. Rare cases of symptomatic postural hypotension, manifested in the form of dizziness (without fainting), have been reported in such patients. In some sensitive patients receiving alpha-blockers, the simultaneous use of sildenafil may lead to symptomatic hypotension.

There were no signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the CYP2C9 isoenzyme.

pharmacokinetics of sildenafil

Sildenafil (100 mg) has no effect on the pharmacokinetics of the HIV protease inhibitor, saquinavir, which is a substrate of the CYP3A4 isoenzyme, at its constant level in the blood.

Simultaneous use of sildenafil at steady state (80 mg 3 times a day) leads to an increase in the AUC and Cmax of bosentan (125 mg 2 times a day) by 49.8 and 42%, respectively.

Sildenafil (50 mg) does not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg).

Sildenafil (50 mg) does not enhance the hypotensive effect of alcohol in healthy volunteers with an average blood alcohol cmax of 0.08% (80 mg/dl).

In patients with hypertension, there were no signs of interaction of sildenafil (100 mg) with amlodipine. The average additional decrease in blood pressure in the supine position is 8 mm Hg (systolic) and 7 mm Hg (diastolic).

The use of sildenafil in combination with antihypertensive agents does not lead to additional side effects.

No Comments

Leave a Reply

Your email address will not be published.