title: Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy.
abstract: 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 as being 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 an 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 to achieve its effective use in RA therapy.
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Inoue
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yuasa
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D018501:Antirheumatic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D001692:Biological Transport; D058976:Folate Receptor 2 / Q000378:metabolism; D006801:Humans; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D027361:Organic Anion Transporters / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D018528:ATP-Binding Cassette Transporters; D018501:Antirheumatic Agents; D058976:Folate Receptor 2; D027361:Organic Anion Transporters; D008727:Methotrexate