Rabeprazole: Drugs Metabolized by CYP450 System: Rabeprazole is metabolized by the cytochrome P-450 (CYP-450) drug metabolizing enzyme system. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP-450 system eg, warfarin and theophylline given as singe oral dose, diazepam as a single IV dose and phenytoin given as a single IV dose (with supplemental oral dosing). Steady-state interactions of rabeprazole and other drugs metabolized by this enzyme system have not been studied in patients. There have been reports of increased international normalized ratio (INR) and prothrombin time in patients receiving proton-pump inhibitors, including rabeprazole and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Cyclosporine: In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with rabeprazole 20 mg. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.
Antacids: Co-administration of rabeprazole and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.
Other: Rabeprazole produces sustained inhibition of gastric acid secretion. An interaction with compounds which are dependent on gastric pH for absorption may occur due to the magnitude of acid suppression observed with rabeprazole. For example, in normal subjects, co-administration of rabeprazole 20 mg once daily resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increase in the AUC and Cmax for digoxin of 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole.
Domperidone: CYP3A4 Inhibitors: The main metabolic pathway of domperidone is through CYP3A4. In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone. In vivo interaction studies with ketoconazole revealed a marked inhibition of domperidone's CYP3A4-mediated first pass metabolism by ketoconazole.
A pharmacokinetic study has demonstrated that the AUC and the peak plasma concentration of domperidone is increased by a factor 3 when oral ketoconazole is administered concomitantly (at steady state). A slight QT prolonging effect (mean <10 msec) of this combination was detected, which was greater than the 1 seen with ketoconazole alone. A QT prolonging effect could not be detected when domperidone was given alone in patients with no co-morbidity, even at high oral doses (up to 160 mg/day).
The results of this interaction study should be taken into account when prescribing domperidone concomitantly with strong CYP3A4 inhibitors eg, ketoconazole, ritonavir and erythromycin.