The processes of sildenafil metabolism are mainly carried out with the isoform of ZA4 (is the main route), and in addition the 2S9 isoform (used as a secondary pathway) of the hemoprotein P450 (CYP). As a result, inhibitors of these isoenzymes are able to reduce the clearance of the substance, while their inductors, on the contrary, increase it.
Reduction in the values of clearance of sildenafil arose as a result of a combination with inhibitors of the element CYP3A4 (among them cimetidine with ketoconazole, as well as erythromycin). Although there was no increase in the development of negative symptoms in such treated patients, it is recommended to consider the variant with Vekta intake in the initial dosage of 25 mg with a similar combination.
When combined use of drugs (a single use of 100 mg) with a component of ritonavir, an HIV protease inhibitor (this is an extremely potent inhibitor of the P450 element), which is used in equilibrium (a single dose of 500 mg per day), an increase in the peak level of sildenafil (quadruple 300%), and in addition the plasma value of AUC substance (11 times - by 1000%). After 24 hours, the plasma values of the component still remained at approximately 200 ng / ml, compared to a figure of about 5 ng / ml, which is usually observed when only sildenafil is used. This corresponds to a significant effect of ritonavir substance on a large range of substrates such as P450. The active component of Vecta does not affect the pharmacokinetic parameters of ritonavir. Due to all the above, it can be concluded that the combination of these drugs is prohibited. In any case, if you used this combination, you still should not take sildenafil in a period of 48 hours in a dosage that exceeds the value of 25 mg.
Drug administration (once 100 mg) in combination with saquinavir (HIV protease inhibitor and CYP3A4 element), in a dosage that allows to achieve equilibrium values of the substance (1200 mg - three times per day), causes an increase in the peak level of the active component of the Vecta by 140%, and also AUC values (by 210%). Sildenafil has no effect on the various pharmacokinetic parameters of the saquinavir component. There are suggestions that stronger inhibitor drugs of the element CYP3A4 (among them itraconazole or ketoconazole) will have more pronounced properties.
The use of a single dose (100 mg) of sildenafil with an inhibitory agent of a moderate-type CYP3A4 element, erythromycin (equilibrium use of 500 mg twice daily for a period of 5 days), led to a 182% increase in the AUC level of the active drug component.
In male volunteers, when 500 mg of azithromycin was taken, during 3 days, the effect on the AUC, the peak level, the time of its attainment, and also the rate constant of the elimination process and the further half-life of the active component of Vecta or its main circulating decay product were not determined.
The administration of 800 mg of cimetidine (an inhibitor of the hemoprotein P450, and also a non-specific inhibitory drug of the CYP3A4 element) together with 50 mg of the active substance Vekta caused a 56% increase in the indices of the volunteers using the volunteers.
Grapefruit juice can slow down the action of the element CYP3A4 inside the intestinal walls (with a weak effect), and also increase the plasma values of sildenafil (moderately).
Although no tests have been performed to identify specific interactions with all drugs, the results of population pharmacokinetic studies have shown that the properties of sildenafil are not changed in the case of combined use with drugs from the category of inhibitors of the CYP2C9 element (such as warfarin with tolbutamide and phenytoin). In addition, there is no change when combined with drugs from the category of inhibitors of the CYP2D6 component (including selective drugs for inhibiting reverse serotonin uptake and tricyclics), as well as with the category of thiazide, and with it thiazide-like diuretics, calcium antagonists, ACE inhibitors, and in addition to these β-adrenoreceptor antagonist drugs or agents inducing the metabolism of the CYP450 element (among them barbiturates with rifampicin).
The combination with strong inducers of CYP3A4 component (with rifampicin substance) can cause a greater decrease in the plasma level of sildenafil.
The drug nicorandil is a hybrid agent containing nitrates and promoting the activation of Ca channels. Nitrate element suggests the possibility of developing close interaction with the substance sildenafil.
Since there is information that Vekta can affect the metabolism of NO / cGMP, it has been found that sildenafil can enhance the antihypertensive properties of nitrates. As a consequence, it is forbidden to combine the drug with nitrates of any type or with NO donors.
Combined use of drugs with α-adrenoreceptor blocking agents can cause symptomatic type hypotension in individual patients (having a predisposition). Such manifestations often appeared in the period of 4 hours after the use of Vekta.
Combination of a drug with doxazosin in people who achieved stabilization of their condition, using doxazosin, occasionally led to the appearance of an orthostatic collapse of a symptomatic type. At the same time, there were reports of dizziness and development of a pre-fainting condition (but without fainting).
In patients taking sildenafil, there were no changes in the profile of side effects (in comparison with placebo) in the case of combination with the following groups of antihypertensive drugs: ACE inhibitors, diuretics, β-adrenergic blocker drugs, antihypertensive agents with central and vasodilating effect, angiotensin type antagonists 2, and in addition to blockers of Ca channels, adrenergic type neurons, and α-adrenergic receptors.
In special testing of the combined use of sildenafil (100 mg) with amlodipine, an additional reduction (by 8 mm Hg) of the systolic blood pressure level was observed in persons with elevated blood pressure when lying down. The decrease in the diastolic blood pressure was 7 mm Hg.
In male volunteers, taking medications at the equilibrium concentration (three times per day 80 mg) increased the AUC and the peak level of the substance bosentan (twice daily 125 mg per day) by 49.8% and 42%, respectively.