Incidence of Drug Interaction When Using Proton Pump Inhibitor and Warfarin According to Cytochrome P450 2C19 (CYP2C19) Genotype in Japanese

OBJECTIVES: The US Food and Drug Administration has suggested that proton pump inhibitors (PPIs) increase the international normalized ratio (INR) when used concomitantly with warfarin (WF) because of being metabolized by cytochrome P450 2C19 (CYP2C19). We assessed whether CYP2C19 genotypes and type of PPI accentuated the drug interaction. METHODS AND RESULTS: The study group was 82 patients who needed WF after surgery and had their CYP2C19 genotypes analyzed in advance. We randomly divided them into two groups: group I (n = 41) included patients who had lansoprazole 15 mg/day and group II (n = 41) included patients who had rabeprazole 10 mg/day. The dose of WF was controlled by the doctor in charge as a target INR of 1.6 to 2.6 during the 2 months after surgery. The maximum INR was significantly higher in group I (3.36 ± 0.98) than in group II (2.29 ± 0.55, p < 0.0001). The incidence of over-INR (> 3.5) was significantly higher in group I (15 cases) than in group II (2 cases, p = 0.0001). Several bleeding events complicated 10 patients in group I, but none in group II (p = 0.015). Logistic regression analysis revealed that over-INR (odds ratio [OR] 3.58, 95% confidence interval [CI]: 3.48-368.25, p < 0.0001), and pair of lansoprazole and CYP2C19 intermediate metabolizer (OR 2.39, 95% CI: 1.108-29.491, p = 0.0009) were independent predictors of bleeding events. CONCLUSION: If a patient has had the intermediate metabolizer CYP2C19 genotype and concomitant use of WF and a PPI after open heart surgery, lansoprazole intensifies the effects of WF and is associated with bleeding events.