Physicochemical parameters responsible for the affinity of methotrexate analogs for rat canalicular multispecific organic anion transporter (cMOAT/MRP2)

Pharm Res. 2001 May;18(5):579-86. doi: 10.1023/a:1011064806507.


Purpose: Canalicular multispecific organic anion transporter (cMOAT/MRP2) is known to exhibit a broad substrate specificity toward amphiphatic organic anions, including methotrexate (MTX). The present study aims to identify the physicochemical properties of MTX derivatives that correlate with recognition specificity by cMOAT/MRP2.

Methods: We examined the inhibitory effect of MTX and 24 analogs on the transport of [3H]-S-(2,4-dinitrophenyl)glutathione by cMOAT/MRP2. The affinity constants of these compounds were compared with their physicochemical parameters. The primary active transport of several compounds was also confirmed.

Results: The affinity constants closely correlated with the octanol/water partition coefficient (clogP), and a linear combination of polar and nonpolar surface areas. The affinity for cMOAT/MRP2 also closely correlated with the molecular weight, which also showed a significant correlation with nonpolar surface area and clogP.

Conclusions: Recognition by cMOAT/MRP2 depends on a balance of dynamic surface properties between the polar and nonpolar regions of MTX analogs. The so-called "molecular weight threshold" for the cMOAT/MRP2 affinity of these compounds can be explained by their physicochemical parameters, especially their nonpolar surface areas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antimetabolites, Antineoplastic / chemistry*
  • Antimetabolites, Antineoplastic / metabolism*
  • Bile Canaliculi / metabolism*
  • Chemical Phenomena
  • Chemistry, Physical
  • In Vitro Techniques
  • Kinetics
  • Linear Models
  • Male
  • Membrane Transport Proteins*
  • Methotrexate / analogs & derivatives*
  • Methotrexate / chemistry
  • Methotrexate / metabolism
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Surface Properties


  • Antimetabolites, Antineoplastic
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • Adenosine Triphosphate
  • multidrug resistance-associated protein 1
  • Methotrexate