Exploring Ilaprazole-CYP2C19 interaction: A computational study on metabolic stability and drug-drug interaction potential

Abstract

Background:Proton pump inhibitors (PPIs) have been shown to reduce the therapeutic efficacy and alter the clinical outcomes of co-administered medications due to cytochrome P450 family 2 subfamily C member 19 (CYP2C19) enzyme inhibition. Compared with conventional PPIs, Ilaprazole may have a minimal or negligible inhibitory effects on CYP2C19, potentially lowering the risk of drug-drug interactions, as per the results of preliminary studies and its pharmacokinetic variability.
Objective:This study aimed to evaluate the CYP2C19 interaction potential of ilaprazole versus conventional PPIs using a computational approach (SuperCYP and SMARTCyp).
Study design: This was a computational in silico study combining database-driven predictions (SuperCYP) with structure-based metabolism modeling (SMARTCyp).
Methods:Computational techniques such as SuperCYP predict cytochrome P450 (CYP450) interactions (inhibition, induction, or substrate affinity) of drugs and SMARTCyp predicts sites of metabolism (SOM) in small molecules by CYP450 enzymes, specifically identifying vulnerable atoms within drug structure.
Results:Based on MORGAN and MACCS fingerprints, ilaprazole was predicted to be inactive for CYP2C19 inhibition, with a low probability value (0.552-0.587) using cytochrome enzyme inhibition activity. SMARTCyp predicts SOM by the cytochrome P450 family 3 subfamily A member 4 (CYP3A4) enzyme, where a lower 3A4 ranking and score (S.9 with 41.5) indicate a higher probability of metabolism, and lower energy values (S.9 with 46.9) suggest increased reactivity. Higher 2DSASA values (C.26 with 64.3) indicated stronger enzyme-substrate interactions.
Conclusion:This study supports the hypothesis that ilaprazole does not inhibit CYP2C19, as evidenced by its low probability and inactivity predictions.

Keywords

Ilaprazole / Enzyme inhibition / Proton pump inhibitor / Computational approach / CYP2C19 / CYP3A4 / Drug-drug interaction

Ethics approval

Not applicable.

Funding

None.

CRediT authorship contribution statement

Priyadharshini Ananthathandavan: Formal analysis, Writing - original draft, Methodology, Data curation. Damodharan Narayanasamy: Validation, Supervision, Conceptualization, Formal analysis, Writing - review and editing.

Declaration of Competing Interest

The authors declare no competing financial interests or personal relationships, including employment, consultancies, stock ownership, honoraria, paid expert testimony, patents (granted or pending), or other affiliations with any organization or entity whose subject matter is discussed in this manuscript.

Acknowledgment

Authors thank the SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, for providing technical resources. The figures in the manuscript were originally created by the authors using Microsoft PowerPoint without the use of any specialized software, copyrighted elements, or reprinted materials. Therefore, no copyright permission is required.

Data Availability Statement

The data supporting the findings of this study are available upon reasonable request from the corresponding author.

References

[1] Scarpignato C, Gatta L, Zullo A, et al. Effective and safe proton pump inhibitor therapy in acid-related diseases: a position paper addressing benefits and potential harms of acid suppression. BMC Med. 2016; 14(1):179. https://doi.org/10.1186/s12916-016-0718-z

[2] Li Y, Zhang W, Guo D, Zhou G, Zhou H, Xiao Z. Pharmacokinetics of the new proton pump inhibitor ilaprazole in Chinese healthy subjects in relation to CYP3A5 and CYP2C19 genotypes. Clin Chim Acta. 2008; 391(1-2):60-67. https://doi.org/10.1016/j.cca.2008.02.003

[3] Bouziana SD. Tziomalos K. Clinical relevance of clopidogrel-proton pump inhibitors interaction. World J Gastrointest Pharm Ther. 2015; 6(2):17-21. https://doi.org/10.4292/wjgpt.v6.i2.17

[4] Choi YJ, Kim N, Jang IJ, et al. Pantoprazole does not reduce the antiplatelet effect of clopidogrel: a randomized controlled trial in korea. Gut Liver. 2017; 11(4):504-511. https://doi.org/10.5009/gnl16352

[5] Ananthathandavan P, Narayanasamy D. Computational drug-drug interaction prediction mediated by CYP450 isoforms of ilaprazole coadministered with clopidogrel. Future Sci OA. 2024; 10(1):FSO966. https://doi.org/10.2144/fsoa-2023-0277

[6] Seo KA, Lee SJ, Kim KB, et al. Ilaprazole, a new proton pump inhibitor, is primarily metabolized to ilaprazole sulfone by CYP3A4 and 3A5. Xenobiotica. 2012; 42(3):278-284. https://doi.org/10.3109/00498254.2011.622416

[7] Pu J, Wang F, Tang W, Zhu M. Biotransformation of ilaprazole in human liver microsomes and human: role of CYP3A4 in ilaprazole clearance and drug-drug interaction. Drug Metab Dispos. 2018; 46(10):1453-1461. https://doi.org/10.1124/dmd.118.081570

[8] De Bortoli N, Martinucci I, Giacchino M, et al. The pharmacokinetics of ilaprazole for gastro-esophageal reflux treatment. Expert Opin Drug Metab Toxicol. 2013; 9(10):1361-1369. https://doi.org/10.1517/17425255.2013.813018

[9] Ananthathandavan P, Narayanasamy D. In-silico assessment of CYP2C19 and CYP3A4 inhibitory potential of ilaprazole. Res J Pharm Technol. 2025; 18(3):1113-1117. https://doi.org/10.52711/0974-360X.2025.00160

[10] Jin BH, Yoo BW, Park J, et al. Pharmacokinetic drug interaction and safety after coadministration of clarithromycin, amoxicillin, and ilaprazole: a randomised, open- label, one-way crossover, two parallel sequences study. Eur J Clin Pharm. 2018; 74(9):1149-1157. https://doi.org/10.1007/s00228-018-2489-2

[11] Preissner S, Kroll K, Dunkel M, et al. SuperCYP: a comprehensive database on cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010;38:D237-D243. https://doi.org/10.1093/nar/gkp970

[12] Sabarathinam S, Ganamurali N. Chalcones reloaded: an integration of network pharmacology and molecular docking for type 2 diabetes therapy. J Biomol Struct Dyn. 2024; 42(18):9505-9517. https://doi.org/10.1080/07391102.2023.2252085

[13] Banerjee P, Dunkel M, Kemmler E, Preissner R. SuperCYPsPred-a web server for the prediction of cytochrome activity. Nucleic Acids Res. 2020; 48(W1):W580-W585. https://doi.org/10.1093/nar/gkaa166

[14] Rydberg P, Gloriam DE, Zaretzki J, Breneman C, Olsen L. SMARTCyp: a 2D method for prediction of cytochrome P450-Mediated drug metabolism. ACS Med Chem Lett. 2010; 1(3):96-100. https://doi.org/10.1021/ml100016x

[15] Ananthathandavan P, Narayanasamy D. Delineating CYP2C19-mediated interactions: network pharmacology investigation of ilaprazole and clopidogrel versus conventional proton pump inhibitors. Curr Drug Discov Technol. 2025; 22(3):e15701638334244. https://doi.org/10.2174/0115701638334244241224062453

[16] Priyadharshini A, Vijayakumar TM, Damodharan N, Vasanth KM, Elaiyaraja A. Comparative in vitro assessment of CYP2C19 inhibition by ilaprazole and conventional proton pump inhibitors using a high throughput fluorometric assay. Sci Rep. 2025; 15(1):18158. https://doi.org/10.1038/s41598-025-02872-5

[17] Cho H, Choi MK, Cho DY, et al. Effect of CYP2C19 genetic polymorphism on pharmacokinetics and pharmacodynamics of a new proton pump inhibitor, ilaprazole. J Clin Pharm. 2012; 52(7):976-984. https://doi.org/10.1177/0091270011408611

[18] Castus HI, Amanan B, Murugadoss H, Ananthathandavan P. Ilaprazole: distinctive pharmacokinetic and pharmacodynamic properties among proton pump inhibitors. Gastroenterol Endosc. 2025; 3(3):184-192. https://doi.org/10.1016/j.gande.2025.04.001

[19] Ye Z, Chen P, Tan C, et al. Effects of ilaprazole on the steady-state pharmacodynamics of clopidogrel in healthy volunteers: an open-label randomized crossover study. Front Pharm. 2022;13:952804. https://doi.org/10.3389/fphar.2022.952804

[20] Wang H, Shao F, Liu X, et al. Efficacy, safety, and pharmacokinetics of ilaprazole infusion in healthy subjects and patients with esomeprazole as a positive control. Br J Clin Pharm. 2019; 85(11):2547-2558. https://doi.org/10.1111/bcp.14076

[21] Funck-Brentano C, Szymezak J, Steichen O, et al. Effects of rabeprazole on the antiplatelet effects and pharmacokinetics of clopidogrel in healthy volunteers. Arch Cardiovasc Dis. 2013; 106(12):661-671. https://doi.org/10.1016/j.acvd.2013.09.002