The association between anti-acid use and tyrosine kinase inhibitor-induced hepatotoxicity
Mohammadsalman Parsapour1, Hamed Ghiami1, Navid Omidkhoda2
1Department of Pharmacy, Damghan Branch, Islamic Azad University, Damghan, Iran.
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.
Insights
The combination of tyrosine kinase inhibitors (TKIs) with acid suppressants (AS) can alter liver toxicity. Effects vary by TKI, necessitating careful patient monitoring during co-treatment.
Area of Science:
- Pharmacology
- Hepatology
- Drug Interactions
Background:
- Tyrosine kinase inhibitors (TKIs) are crucial cancer therapeutics.
- Acid suppressants (AS) are frequently co-administered with TKIs.
- Potential drug interactions affecting hepatotoxicity require investigation.
Purpose of the Study:
- To investigate hepatotoxicity changes with concomitant TKI and AS use.
- To elucidate the underlying mechanisms of these drug interactions.
Main Methods:
- Systematic literature search of PubMed, Scopus, and Web of Science databases.
- Data extraction and analysis of hepatotoxicity alterations and mechanisms.
- Focus on specific TKIs (gefitinib, erlotinib, crizotinib, lapatinib, imatinib, nilotinib, pazopanib, cabozantinib) and AS (PPIs, H2RAs).
Main Results:
- Increased hepatotoxicity observed with gefitinib, erlotinib, crizotinib, and lapatinib due to transporter inhibition (ABCB1, ABCG2).
- Imatinib showed variable effects: increased hepatotoxicity with PPIs, decreased with H2RAs.
- Nilotinib showed decreased hepatotoxicity due to reduced absorption; pazopanib and cabozantinib had no significant changes.
Conclusions:
- Hepatotoxicity impact of TKI-AS coadministration is TKI-specific.
- Pharmacokinetic characteristics influence the interaction outcomes.
- Clinical monitoring is essential for managing these potential interactions.
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