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Expression, Detergent Solubilization, and Purification of a Membrane Transporter, the MexB Multidrug Resistance Protein
10:43

Expression, Detergent Solubilization, and Purification of a Membrane Transporter, the MexB Multidrug Resistance Protein

Published on: December 3, 2010

Increasing systemic exposure of methotrexate by active efflux mediated by multidrug resistance-associated protein 3

Yoshiaki Kitamura1, Masakazu Hirouchi, Hiroyuki Kusuhara

  • 1Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

The Journal of Pharmacology and Experimental Therapeutics
|August 23, 2008
PubMed

Insights

Multidrug resistance-associated protein 3 (Mrp3) significantly impacts methotrexate pharmacokinetics by mediating basolateral efflux in the liver and duodenum, increasing systemic exposure. Mrp4 plays a minor role.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Biochemistry

Background:

  • Multidrug resistance-associated proteins (Mrps) are crucial efflux transporters involved in drug disposition.
  • Understanding the role of Mrp3 and Mrp4 in methotrexate pharmacokinetics is essential for optimizing its therapeutic use.

Purpose of the Study:

  • To investigate the functional significance of Mrp3 (Abcc3) and Mrp4 (Abcc4) in the pharmacokinetics of methotrexate.
  • To elucidate the specific transport mechanisms and sites of action for Mrp3 and Mrp4 in methotrexate disposition.

Main Methods:

  • Pharmacokinetic studies in wild-type, Abcc3(-/-), and Abcc4(-/-) mice.
  • Oral and intravenous administration of methotrexate.
  • Determination of plasma concentrations and pharmacokinetic parameters.
  • In vitro everted sac experiments to assess mucosal-to-serosal transport.

Main Results:

  • Oral methotrexate plasma concentrations were significantly lower in Abcc3(-/-) mice compared to wild-type mice.
  • Biliary clearance of methotrexate was 1.6-fold greater in Abcc3(-/-) mice, indicating altered hepatobiliary transport.
  • Reduced basolateral efflux clearance in the liver and decreased serosal membrane efflux clearance in the duodenum of Abcc3(-/-) mice were observed.
  • Mrp4 knockout mice showed similar plasma concentrations to wild-type mice, suggesting a limited role.

Conclusions:

  • Mrp3 plays a significant role in the basolateral efflux of methotrexate in the liver and duodenum, contributing to increased systemic exposure.
  • Mrp4 appears to have a limited role in systemic methotrexate exposure.
  • These findings highlight Mrp3 as a key transporter influencing methotrexate pharmacokinetics and suggest potential therapeutic implications.

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