Priyadharshini A, Vijayakumar T M, Damodharan N, Vasanth K M, Elaiyaraja Arun
Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, Tamil Nadu, 603203, India.
Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, Tamil Nadu, 603203, India.
Sci Rep. 2025 May 25;15(1):18158. doi: 10.1038/s41598-025-02872-5.
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/K, 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, values, was found to be: Omeprazole > Lansoprazole > Pantoprazole > Rabeprazole > Ilaprazole. The results of the C/K, 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.
质子泵抑制剂（PPIs）是常用的抗溃疡药物，已知其会抑制CYP2C19，从而导致药代动力学药物相互作用（DDIs）。艾普拉唑是一种新型PPI，具有独特的药代动力学特征，预计可克服CYP2C19抑制作用。本研究旨在使用高通量荧光测定法预测艾普拉唑与传统PPIs（奥美拉唑、兰索拉唑、泮托拉唑和雷贝拉唑）对CYP2C19活性的CYP2C19抑制潜力。使用了Vivid™ CYP2C19蓝色筛选试剂盒，并在与PPIs孵育后测量荧光强度，使用噻氯匹定作为阳性抑制剂对照。计算抑制百分比，并在GraphPad Prism中使用非线性回归分析确定IC50值，此外，根据监管指南，评估C/K比值以解释PPIs临床药物相互作用的可能性。评估了所有PPIs对CYP2C19活性的浓度依赖性抑制作用。根据IC50和K值，抑制效力顺序为：奥美拉唑＞兰索拉唑＞泮托拉唑＞雷贝拉唑＞艾普拉唑。C/K比值结果表明，奥美拉唑（0.0288）超过了与其体内CYP2C19抑制作用充分记录一致的临界值。虽然兰索拉唑（0.00332）的比值相对高于艾普拉唑（0.00224）、泮托拉唑（0.00124）和雷贝拉唑（0.000635），但所有值均低于监管临界值，表明抑制风险最小。奥美拉唑是最有效的CYP2C19抑制剂，因为它超过了体外研究的监管阈值指南，而其他测试的PPIs，包括艾普拉唑，未达到此临界值，表明临床显著抑制的可能性较低。尽管先前的体内研究表明其他PPIs的抑制作用存在差异，但当前数据支持需要进行进一步的直接体内比较，特别是泮托拉唑、雷贝拉唑和艾普拉唑之间的比较，以确定在涉及CYP2C19底物的临床场景中最合适的选择。
