Methotrexate and Proton Pump Inhibitor: Drug Interaction Guide

Quick answer: This combination requires caution. Methotrexate and Proton Pump Inhibitor can be used together with adjustments and monitoring.

Interaction severity: Moderate — caution required

How Methotrexate interacts with Proton Pump Inhibitor

PPIs inhibit renal tubular secretion of methotrexate via BCRP and MRP transporters, delaying methotrexate clearance and prolonging exposure of its toxic 7-hydroxy metabolite, especially with high-dose regimens.

What you should do

Withhold PPIs during high-dose methotrexate; consider an H2 antagonist (e.g. ranitidine/famotidine) for gastroprotection during low-dose oncology or rheumatology regimens.

Key facts

Severity

Moderate — caution required

Mechanism

PPIs inhibit renal tubular secretion of methotrexate via BCRP and MRP transporters, delaying methotrexate clearance and ...

Action

Withhold PPIs during high-dose methotrexate; consider an H2 antagonist (e.g. ranitidine/famotidine) for gastroprotection...

Important medical disclaimer: This page provides educational information about drug interactions for general reference. It is not a substitute for professional medical advice, diagnosis, or treatment. Always discuss your specific medications with a qualified healthcare provider before starting, stopping, or changing any treatment. About our editorial team.

Frequently asked questions

Can I take Methotrexate and Proton Pump Inhibitor together?

With caution. Withhold PPIs during high-dose methotrexate; consider an H2 antagonist (e.g. ranitidine/famotidine) for gastroprotection during low-dose oncology or rheumatology regimens.

What is the severity of this interaction?

The interaction between Methotrexate and Proton Pump Inhibitor is classified as Moderate — caution required. PPIs inhibit renal tubular secretion of methotrexate via BCRP and MRP transporters, delaying methotrexate clearance and prolonging exposure of its toxic 7-hydroxy metabolite, especially with high-dose regimens.

What should I do if I'm prescribed both?

Withhold PPIs during high-dose methotrexate; consider an H2 antagonist (e.g. ranitidine/famotidine) for gastroprotection during low-dose oncology or rheumatology regimens. Always consult your prescribing clinician — do not stop or change medications without medical guidance.

Last reviewed: by iMedic Medical Editorial Team. Our editorial process.