Comparative in vitro assessment of CYP2C19 inhibition by ilaprazole and conventional proton pump inhibitors using a high throughput fluorometric assay

Proton pump inhibitors (PPIs) are commonly used anti-ulcer agents, known to inhibit CYP2C19, leading to pharmacokinetic drug-drug interactions (DDIs). Ilaprazole is a newer PPI with a distinct pharmacokinetic profile that is predicted to overcome CYP2C19 inhibition. The current study aimed to predict the CYP2C19 inhibitory potential of Ilaprazole versus conventional PPIs (Omeprazole, Lansoprazole, Pantoprazole, and Rabeprazole) on CYP2C19 activity using a high-throughput fluorometric assay. The Vivid™ CYP2C19 Blue Screening Kit was utilized, and fluorescence intensity was measured after incubation with PPIs, using ticlopidine as a positive inhibitor control. The inhibition percentage was calculated, and IC50 values were determined using nonlinear regression analysis in graph pad prism, further, as per regulatory guidance, the C_max,u/K_i,_u ratio was assessed to interpret the potential for clinical drug-drug interactions of PPIs. The concentration-dependent inhibition of CYP2C19 activity by all PPIs was evaluated. The order of inhibition potency, based on IC50 and K_i,_u values, was found to be: Omeprazole > Lansoprazole > Pantoprazole > Rabeprazole > Ilaprazole. The results of the C_max,u/K_i,_u ratio indicate that Omeprazole (0.0288) exceeded the cut-off value consistent with its well-documented in vivo CYP2C19 inhibitory effect. While Lansoprazole (0.00332) had a relatively higher ratio than Ilaprazole (0.00224), Pantoprazole (0.00124), and Rabeprazole (0.000635), all values remained below the regulatory cutoff, indicating minimal inhibition risk. Omeprazole is the most potent CYP2C19 inhibitor, as it exceeded the regulatory threshold guidelines for in vitro study, while other tested PPIs, including Ilaprazole, did not meet this cutoff, suggesting a lower likelihood of clinically significant inhibition. Although previous in vivo studies suggest variable inhibition with other PPIs, current data support the need for further head-to-head in vivo comparisons, particularly between Pantoprazole, Rabeprazole, and Ilaprazole, to determine the most suitable option in clinical scenarios involving CYP2C19 substrate.