Effect of esomeprazole on the pharmacokinetics of other drugs Decrease in secretion of hydrochloric acid in the stomach against the background of treatment with esomeprazole and other inhibitors of the proton pump can lead to a change in the absorption of drugs, the absorption of which depends on the acidity of the medium. Like other drugs that reduce the acidity of gastric juice, treatment with esomeprazole may lead to a decrease in the absorption of ketoconazole, itraconazole and erlotinib and increase the absorption of such drugs as digoxin. Joint omeprazole 20 mg once a day and digoxin increases the bioavailability of digoxin by 10% (the bioavailability of digoxin was increased by up to 30% in 2 of 10 patients).
It was shown that omeprazole interacts with some antiretroviral drugs. The mechanisms and clinical significance of this interaction are not always known. An increase in pH on the background of omeprazole therapy may affect the absorption of antiretroviral drugs. It is also possible to interact at the isoenzyme level CYP2C19. With the joint use of omeprazole and some antiretroviral drugs, such as atazanavir and nelfinavir, against the background of therapy with omeprazole, there is a decrease in their concentration in the serum. Therefore, their simultaneous application is not recommended. The combined use of omeprazole (40 mg once daily) with atazanavir 300 mg / ritonavir 100 mg by healthy volunteers resulted in a significant decrease in the bioavailability of atazanavir (AUC, FROMmOh and the minimum concentration in the blood plasma decreased by approximately 75%). An increase in the dose of atazanavir to 400 mg did not compensate for the effects of omeprazole on the bioavailability of atazanavir.
With the simultaneous use of omeprazole and saquinavir, there was an increase in the concentration of saquinavir in the serum, with the appointment with some other antiretroviral drugs, their concentration did not change. Given the similar pharmacokinetic and pharmacodynamic properties of omeprazole and esomeprazole, the combined use of esomeprazole with antiretroviral drugs, such as atazanavir and nelfinavir, Not recommended.
Esomeprazole inhibits isoenzyme CYP2C19 - the main isoenzyme involved in its metabolism. Accordingly, the joint use of esomeprazole with other drugs in the metabolism of which isoenzyme participates CYP2C19 (such as diazepam, citalopram, imipramine, clomipramine, phenytoin , etc.), can lead to an increase in the concentrations of these drugs in the blood plasma, which, in turn, may require a dose reduction. It is especially important to remember about this interaction when using esomeprazole in the "if necessary" therapy regimen. With the joint ingestion of esomeprazole in a dose of 30 mg and diazepam, which is the substrate of the isoenzyme CYP2C19, there is a decrease in clearance of diazepam by 45%.
The use of esomeprazole at a dose of 40 mg caused an increase in the residual concentration of phenytoin in patients with epilepsy by 13%. In this regard, it is recommended to control the concentration of phenytoin in the blood plasma at the beginning of treatment with esomeprazole and when it is withdrawn.
The use of omeprazole at a dose of 40 mg once a day led to an increase AUC and CmOh voriconazole (substrate isoenzyme CYP2C19) by 15% and 41% respectively. The simultaneous administration of warfarin with esomeprazole at a dose of 40 mg does not lead to a change in coagulation time in patients taking long-term warfarin. However, several cases of a clinically significant increase in the index of the international normalized relationship were reported when combined with warfarin and esomeprazole. It is recommended to monitor the INR at the beginning and after the end of the joint use of esomeprazole and warfarin or other coumarin derivatives.
The pharmacokinetic / pharmacodynamic interaction between clopidogrel (loading dose 300 mg and maintenance dose 75 mg / day) and esomeprazole (40 mg / day inwards), which leads to a decrease in the exposure of the active metabolite of clopidogrel by an average of 40% and a decrease in the maximum inhibition ADP-induced platelet aggregation is on average 14%. The clinical significance of this interaction is not clear. In a prospective study in patients receiving placebo or omeprazole in a dose of 20 mg / day simultaneously with clopidogrel and acetylsalicylic acid (ACA) therapy, and in the analysis of clinical outcomes of large-scale randomized trials, there was no evidence of an increased risk of cardiovascular complications in the combined use of clopidogrel and proton pump inhibitors, including esomeprazole.
The results of a number of observational studies are contradictory and do not give an unambiguous answer about the presence or absence of an increased risk of thromboembolic cardiovascular complications against the background of joint use of clopidogrel and proton pump inhibitors.
When clopidogrel was used together with a fixed combination of 20 mg of esomeprazole and 81 mg of ASA, the exposure of the active metabolite of clopidogrel decreased by almost 40% compared to clopidogrel alone, with the maximum levels of inhibition of ADP-induced platelet aggregation being the same, probably due to simultaneous administration ASA in a low dose.
The use of omeprazole in a dose of 40 mg resulted in an increase in CmOh and AUC of cystostaxol by 18% and 26%, respectively; for one of the active metabolites of cilostazol, the increase was 29% and 69%, respectively.
Joint use of cisapride with esomeprazole at a dose of 40 mg leads to an increase in the pharmacokinetic parameters of cisapride in healthy volunteers: AUC - by 32% and T1/2 - by 31%, however, CmOh Cisapride in the blood plasma at the same time does not change significantly. Slight lengthening of the interval QT, which was observed with monotherapy with cisapride, did not increase with addition of esomeprazole (see section Special instructions).
With the simultaneous use of esomeprazole and tacrolimus, an increase in tacrolimus concentration in serum was noted.
Some patients reported increased concentrations of methotrexate against a background of combined use with proton pump inhibitors. When using methotrexate in high doses should consider the possibility of temporary withdrawal of esomeprazole.
Esomeprazole does not cause clinically significant changes in the pharmacokinetics of amoxicillin and quinidine.
Studies evaluating the joint short-term use of esomeprazole and naproxen or rofecoxib showed no clinically significant pharmacokinetic interaction.
The effect of drugs on the pharmacokinetics of esomeprazole
In the metabolism of esomeprazole, isozymes participate CYP2C19 and CYP3A4. Joint use of esomeprazole with clarithromycin (500 mg 2 times a day), which inhibits the isoenzyme CYP3A4, leads to an increase in the value AUC esomeprazole 2 times. Joint use of esomeprazole and a combined inhibitor of isoenzymes CYP3A4 and CYP2C19, for example, voriconazole, can lead to more than 2-fold increase in the value AUC esomeprazole. In such cases, as a rule, dosage adjustment of esomeprazole is not required. Correction of the dose of esomeprazole may be required in patients with severe impairment of liver function and with prolonged use.
Medicines that induce isoenzymes CYP2C19 and CYP3A4, such as rifampicin and preparations of St. John's wort penetrated, when combined with esomepromazole may lead to a decrease in the concentration of esomeprazole in the blood plasma by accelerating the metabolism of esomeprazole.