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Evaluation of possible pharmacokinetic interaction between methotrexate and proton pump inhibitors in rats

Hinata Ueda1, Katsuya Narumi2, Yu Sato1

  • 1Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan.

Pharmacological Reports : PR
|July 17, 2020
PubMed
Abstract

Insights

Proton pump inhibitors (PPIs) like esomeprazole can inhibit organic anion transporter 3 (OAT3), potentially delaying methotrexate (MTX) elimination. This study investigated PPI effects on MTX clearance via OAT3.

Area of Science:

  • Pharmacology
  • Nephrology
  • Drug Metabolism

Background:

  • Methotrexate (MTX) is renally cleared, with Organic Anion Transporter 3 (OAT3) playing a key role.
  • Conflicting reports exist regarding the impact of proton pump inhibitors (PPIs) on MTX elimination.
  • This study investigates the link between PPIs' inhibitory effects on OAT3 and delayed MTX elimination.

Purpose of the Study:

  • To evaluate the differential inhibitory effects of PPIs on OAT3-mediated MTX transport.
  • To determine if these inhibitory effects correlate with the risk of delayed MTX elimination.

Main Methods:

  • In vitro assessment of PPIs' effects on rat OAT3-mediated MTX uptake using HEK293T cells.
  • In vivo pharmacokinetic studies in rats, assessing plasma MTX concentration-time profiles after co-administration with MTX and various PPIs.

Main Results:

  • PPIs inhibited OAT3-mediated MTX uptake in vitro, with IC50 values ranging from 2.1-5.2 μM.
  • Esomeprazole significantly increased MTX plasma concentration and half-life (t1/2) in rats.
  • Lansoprazole showed a trend towards prolonging MTX levels, while famotidine had minimal impact.

Conclusions:

  • Esomeprazole significantly increases MTX half-life in rats.
  • This effect is potentially mediated by the inhibition of OAT3 by esomeprazole.
Keywords:
Drug–drug interactionEsomeprazoleLansoprazoleMethotrexateOrganic anion transporter 3Proton pump inhibitor

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