A critical review of methotrexate clinical interactions: role of transporters

ABSTRACT

Introduction

Methotrexate (MTX) is an antifolate and immunosuppressive drug prescribed for various malignancies and immune diseases. However, delayed elimination of MTX associated with concomitant use of some medications can lead to severe and lifethreatening adverse effects.

Areas covered

This paper investigated drugMTX interactions that lead to elevated MTX levels and related adverse effects due to the role of transporters. Methotrexate toxicity occurs at both low and high doses administrations. According to the studies we reviewed in this paper, most interaction records with methotrexate occurred with coadministration of indomethacin, ketoprofen, omeprazole, piperacillin/tazobactam, ciprofloxacin, cotrimoxazole, probenecid, and imatinib, mainly due to the role of transporters. However, most studies were performed as case reports or series, and confirming the exact drugmethotrexate interaction still needs further clinical investigations.

Expert opinion

Our findings showed no firm evidence of interactions of proton pump inhibitors (PPIs), levetiracetam, and NSAIDS with MTX. Moreover, patients’ risk factors, hypoalbuminemia, renal failure, third space fluid retention, the elderly, polypharmacy, and transport inhibition are the most critical factors for MTX toxicity. If substitution or temporary discontinuation is not possible, healthcare providers should be aware of interactions, especially in patients with risk factors for MTX toxicity.

KEYWORDS:

• methotrexate
• proton pump inhibitors
• NSAIDs
• TKIs
• interactions
• non-steroidal anti-inflammatory drugs
• tyrosine kinase inhibitors

Article highlights

• Methotrexate is an appropriate medication for the treatment of various malignancies and immune-mediated diseases.

• Several studies have reported that drug-MTX interactions play a significant role in increasing MTX concentrations and related toxicities by inhibiting the transporters responsible for renal excretion of methotrexate.

• NSAIDs, PPIs, penicillins, and levetiracetam have the most reported interactions with methotrexate, however other drugs, such as TKIs, co-trimoxazole, probenecid, have also been stated to decrease MTX elimination.

• The mechanism of MTX-drug interactions includes the inhibition of renal transporters, for instance, hOAT1, hOAT3, MRP, BCRP, RFC, ABCB and SLCO1B1.

• The majority of the research on methotrexate medication interactions were case reports, and studies with larger populations did not include information on toxicity. However, given that methotrexate has adverse effects that can be fatal, patients’ treatment regimens may benefit from being aware of these potential drug interactions.

This box summarizes key points contained in the article.

Acknowledgments

The authors acknowledge the use of Servier Medical Art as a graphical abstract. The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Authorship contributions

Conceptualization: FJ, OA, VRA, HH, Writing-original draft: FJ, AA, SAA, Writing-review and editing: OA, VRA, HH, AA, Approval of the final version: All authors.

Additional information

Funding

This paper was not funded.