title: Interactions with the protein binding of 7-hydroxy-methotrexate in human serum in vitro.
abstract: 7-Hydroxy-methotrexate (7-OH-MTX), the major extracellular methotrexate (MTX) metabolite, is 90-95% bound in human serum, with albumin (HSA) as the major binding protein. Reports of an interaction with concomitantly administered non-steroidal antiinflammatory drugs (NSAIDs) during MTX therapy led us to investigate whether these compounds could reduce the binding of 7-OH-MTX in vitro. Equilibrium dialysis experiments demonstrated that naproxen and indomethacin concentration dependently reduced the binding of 1 microM 7-OH-MTX. After ingestion of 1000 mg naproxen, per cent unbound 7-OH-MTX in sera from volunteers increased 2-3-fold in vitro, positively correlated to naproxen concentrations (P less than 0.00015). In addition, etacrynic acid, bilirubin, sulphamethizole and acetylsalicylic acid displaced 7-OH-MTX from its binding protein(s) in a competitive manner. The data suggest that 7-OH-MTX interacts with several exogenous and endogenous substances associated with HSA in human serum. Displacement of 7-OH-MTX from HSA may contribute to the interaction between NSAIDs and MTX.
authors.affiliation: Department of Pharmacology, University of Tromsø, Norway.
authors.forename: L
authors.initials: L
authors.lastname: Slørdal
authors.forename: G
authors.initials: G
authors.lastname: Sager
authors.forename: R
authors.initials: R
authors.lastname: Jaeger
authors.forename: J
authors.initials: J
authors.lastname: Aarbakke
mesh_terms: D000328:Adult; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000097:blood; D009288:Naproxen / Q000494:pharmacology; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*
chemical_list: D012709:Serum Albumin; D009288:Naproxen; C011864:7-hydroxymethotrexate; D007213:Indomethacin; D008727:Methotrexate