Methotrexate (MTX) is a derivative of folic acid (folate) and commonly used as an anchor drug for the treatment of rheumatoid arthritis (RA). The pharmacokinetics (PK) and pharmacodynamics (PD) of MTX entirely depends on the function of specific transporters that belong to the two major superfamilies, solute carrier transporters and ATP-binding cassette transporters. Several transporters have been identified to be able to mediate the transport of MTX, and suggested to be involved in the disposition in the body and in the regulation of intracellular metabolism in target cells, together with several enzymes involved in folate metabolism. Thus, drug-drug interactions through the transporters and their genetic polymorphisms may alter the PK and PD of MTX, resulting in the interpatient variability of efficacy. This review summarizes the PK and PD of MTX, particularly in relation to RA therapy and focuses on the roles of transporters involved in PK and PD with the aim of facilitating an understanding of the molecular basis of the mechanism of MTX action and to achieve its effective use in RA therapy.
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