Physicochemical parameters responsible for the affinity of methotrexate analogs for rat canalicular multispecific organic anion transporter (cMOAT/MRP2).
OBJECTIVE
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.
Han
Y H
YH
Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
Kato
Y
Y
Haramura
M
M
Ohta
M
M
Matsuoka
H
H
Sugiyama
Y
Y
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry* / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D066298:In Vitro Techniques; D007700:Kinetics; D016014:Linear Models; D008297:Male; D026901:Membrane Transport Proteins; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013499:Surface Properties
D000255:Adenosine Triphosphate; D000964:Antimetabolites, Antineoplastic; D026901:Membrane Transport Proteins; D008727:Methotrexate; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1