Personalized medicine of methotrexate therapy

摘要: 51 Ned Tijdschr Klin Chem Labgeneesk 2012, vol. 37, no. 1 cutaneous (or intramuscular) injections are given when response is insufficient, when patients do not tolerate oral tablets or when compliance is low. Oral MTX is actively absorbed in a capacity-limited process by the proximal jejunum. Because of the relatively short half-live (6-15 hours), inter mittent LD-MTX administration once a week does not lead to accumulation of MTX in plasma and hence, therapeutic drug monitoring is not possible in LD-MTX treatment. Plasma MTX is mainly eliminated by the kidneys; 65-80% is eliminated within 12 hours after administration. Circulating MTX is taken up into cells via the solute carrier 19A1/reduced folate carrier (SLC19A1/RFC) and is add itionally transported into the cell via the solute carrier 46A1/proton coupled folate transporter (SLC46A1/PCFT) and folate receptors (FOLR) 1 and 2 (figure 1)(29). Members of the adenosine triphosphate (ATP) binding cassette (ABC) transporters including ABCB1/P-glycoprotein (P-gp), multidrug resistance proteins (MRP/ABCC) as well as breast cancer resistance protein (BCRP/ABCG2) function as ATP-dependent MTX efflux transporters (29) albeit with dif ferent affinity. Intracellularly, MTX is polyglutamylated (MTX-PG) by folyl-polyglutamate synthetase (FPGS) to a variability of chain-lengths (PG2-6) competing with γ-glutamyl hydrolase (GGH) that deconjugates glutamate residues (figure 1)(30). Polyglutamylation retains MTX intracellularly because it is no substrate for the MTX efflux proteins and a higher degree of MTX polyglutamylation leads to stronger inhibition of the target enzymes in one-carbon …