Objective: This study aimed to investigate changes in hepatotoxicity associated with the concomitant use of tyrosine kinase inhibitors (TKIs) with Acid suppressants (AS), and to explain the underlying mechanisms. Data Sources: The PubMed, Scopus and Web of Science databases were searched up to July 1, 2025. We started the search on May 1, 2025. Relevant data on hepatotoxicity alternations and their associated mechanisms were extracted and analyzed. Data Summary: Concomitant use of gefitinib, erlotinib, crizotinib and lapatinib with antacids (proton pump inhibitors or H2 receptor antagonists) was associated with increased hepatotoxicity. This effect is attributed to hepatic drug accumulation due to the inhibition of efflux transporters (ABCB1 and ABCG2), which outweighs the reduction in drug absorption caused by elevated gastric pH. Imatinib, showed divergent results: increased hepatotoxicity when combined with PPIs but reduced hepatotoxicity with H2RAs, likely due to additional transporter-related interactions. In the case of nilotinib, reduced drug absorption resulting from increased gastric pH appeared to be the dominant mechanism, leading to decreased hepatotoxicity. For TKIs such as pazopanib and cabozantinib, no significant change in hepatotoxicity was observed with AS coadministration. Conclusion: The impact of coadministration of TKIs with antacids on hepatotoxicity varies depending on the specific TKI and its pharmacokinetic characteristics. These interactions highlight the need for careful evaluation and monitoring in clinical practice.
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