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.

FOLH1/GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities

“…It is possible that elevated folate hydrolase activity in IBD provides improved folate availability from the gut to support nucleotide biosynthesis and cell division of inflammatory cells. In support of this possibility, antifolate drugs such as methotrexate are an effective IBD treatment (45). Finally, there is a possible antiangiogenic effect of FOLH1 / GCPII inhibition in IBD.…”

Folic acid and its metabolite codetermination for pharmacokinetics with circadian rhythms and evaluation of oral bioavailability

“…As for the pharmacokinetic study, codetermination of free FA and its various metabolites, especially for the 5‐methylTHF, is important to investigate the real plasma concentration–time curve after administration of FA. However, the matrix effect and instability of folates are the main challenges for establishing a special, stable and sensitive method, because of the high fundamental level in blank plasma and easily degraded under common conditions . In addition, the methods including microorganism method, radioimmunoassay, high‐performance liquid chromatography (HPLC) and electroanalysis have been reported for codetermination of FA and its metabolites, whereas the complicated sample treatment or the poor sensitivity is a shortcoming for hindering their further application.…”

Genetic Determinants of Methotrexate Toxicity in Tunisian Patients with Rheumatoid Arthritis: A Study of Polymorphisms Involved in the MTX Metabolic Pathway

“…MTX is an anti-folate drug with anti-proliferative and anti-inflammatory effects, due to the inhibition of several key enzymes involved in folate, methionine, adenosine and de novo nucleotide synthesis pathways [7]. However, the exact mechanism of action of MTX is still not fully understood.…”