Objective: Proton pump inhibitors (PPIs) are frequently coadministered with calcineurin inhibitors (CNIs) such as tacrolimus (TAC) and cyclosporin A (CSA), to treat or prevent upper gastrointestinal complications in Japanese patients with connective tissue diseases (CTDs). The coadministration of PPIs increases the blood concentration of TAC due to drug interaction. We retrospectively investigated the influence of the coadministration of PPIs and CNIs, as well as the influence of the cytochrome P450 (CYP) 2C19 gene polymorphism status, on the blood concentrations of TAC and CSA in patients with CTDs.
Methods: Patients treated with TAC (n=35) or CSA (n=30) were enrolled and divided into three groups according to the PPI they received: lansoprazole (LPZ)-combined, rabeprazole (RPZ)-combined, and non-PPI-combined groups. We compared the blood concentrations of TAC or CSA and the incidences of adverse events among the three groups. CYP2C19 gene polymorphisms were also assessed to investigate its influence on the blood concentration of TAC or CSA.
Results: LPZ significantly increased the blood concentration of TAC 12 hours after TAC administration (p=0.030 and p=0.003, respectively) and CSA (p=0.047 and p=0.014, respectively) in comparison with RPZ and non-PPI-combined treatment. There were no significant differences in the mean CSA blood concentration two hours after administration in patients with or without PPI treatment, in the incidence of adverse events, or in the CYP2C19 gene polymorphism status among the three groups.
Conclusion: Combining agents that are mainly metabolized by CYP3A4 such as LPZ elevates the blood concentrations of TAC and CSA, which could leading to adverse events.
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