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Objective: To investigate the ability of the novel proton pump inhibitor rabeprazole to induce cytochrome P450 (CYP) isoenzymes and inhibit CYP3A-mediated cyclosporin metabolism in vitro. Methods: Microsomes were isolated from cultured human hepatocytes that were incubated with rabeprazole, omeprazole and reference CYP1A2 and CYP3A4 inducers. CYP1A2, CYP2D6, CYP2E1 and CYP3A4 were determined by Western blot analysis, and CYP1A and CYP3A monoxygenase activity were determined by enzyme assays. The metabolism of cyclosporin by human liver microsomes in the presence and absence of rabeprazole and omeprazole were also compared. Results: Rabeprazole (50 µmol/L) did not induce accumulation of CYP1A2 or increase CYP1A monoxygenase activity in cultured human hepatocytes, whereas omeprazole (50 µmol/L) induced both CYP1A2 accumulation and its associated monoxygenase activity. Rabeprazole modestly induced CYP3A4 and the associated monoxygenase activity in one of three hepatocyte cultures, whereas omeprazole induced CYP3A4 in all three cultures and monoxygenase activity in one culture. At high drug concentrations, both rabeprazole and omeprazole inhibited cyclosporin metabolism by human liver microsomes in a concentration-dependent manner; the concentration of drug that inhibited cyclosporin metabolism by 50% (IC) values were 62 and 101 µmol/L, respectively. Conclusions: Rabeprazole may have lower potential than omeprazole for causing CYP-mediated drug interactions, inasmuch as it does not induce CYP1A2 and only modestly induces CYP3A4 at high concentrations. At concentrations above what would be expected in humans with a 20mg dose, rabeprazole, like omeprazole, inhibits CYP3A-mediated cyclosporin metabolism. [ABSTRACT FROM AUTHOR]