The interindividual variability in MTX pharmacokinetics can be explained partially by genetic variations in membrane transporter proteins with an affinity for MTX [Articles:19901119, 17112803]. In the gastrointestinal tract, MTX is absorbed through active transport mediated by the reduced folate carrier (SLC19A1) and possibly also by the proton-coupled folate transporter SLC46A1 (HCP1, PCFT) at the apical membrane of enterocytes [Article:17129779]. Furthermore, the bioavailability of MTX after oral dosing may be affected by ABC transporters, which can move MTX out of the enterocytes and back into the intestinal tract (ABCC2, ABCB1, and ABCG2) or into the blood (ABCC1 and ABCC3)[Articles:18464048, 17273943, 14706810]. Systemic clearance of MTX happens primarily through renal glomerular filtration and active secretion over the proximal tubular cells. Several renal transporter proteins have an affinity for MTX (SLC22A6, SLC22A8, SLC19A1, ABCG2, ABCC2, and ABCC4), and single-nucleotide polymorphisms (SNPs) in ABCC2 have been associated with delayed MTX clearance [Articles:17112803, 17005917, 15864128, 15548848, 11856762, 17660957, 19996279]. Hepatic uptake of MTX involves the SLCO1B1 and SLCO1B3 transporters, in which SNPs have recently been found to explain up to 10% of the interpatient variability in the clearance of high-dose MTX [Articles:19901119, 10358072, 11375950, 19022939]. Most of the MTX in hepatocytes re-enters the blood circulation by transporter proteins (ABCC3 and ABCC4) in the basolateral membrane, and only a small portion of the MTX is excreted into the bile duct via ABCC2 and ABCB1 transporters [Articles:18719291, 16611851, 19088030, 19383815].
Mikkelsen Torben S, Thorn Caroline F, Yang Jun J, Ulrich Cornelia M, French Deborah, Zaza Gianluigi, Dunnenberger Henry M, Marsh Sharon, McLeod Howard L, Giacomini Kathy, Becker Mara L, Gaedigk Roger, Leeder James Steven, Kager Leo, Relling Mary V, Evans William, Klein Teri E, Altman Russ B. "PharmGKB summary: methotrexate pathway" Pharmacogenetics and genomics (2011).
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