title: Dexamethasone reduces methotrexate biliary elimination and potentiates its hepatotoxicity in rats.
abstract: Increased hepatotoxicity of methotrexate has been reported during dexamethasone therapy in humans. Despite the observed inducing effect of dexamethasone on some methotrexate transporting proteins in the liver, the kinetic aspects of this interaction have not been studied yet. Thus, the aim of the present study was to evaluate the influence of dexamethasone on the hepatic and overall pharmacokinetics of methotrexate. Pharmacokinetics of methotrexate was evaluated in rats during an in vivo steady-state clearance study after either single intravenous dose of dexamethasone or its four-day oral administration in a dose optimized for transport proteins induction. Dexamethasone oral pretreatment reduced biliary clearance of methotrexate by 53%. Although liver tissue concentration of methotrexate increased only slightly in these animals, a significant increase in liver weights produced by dexamethasone pretreatment revealed a marked increase in liver content of the drug. An evaluation of plasma liver enzyme activities measured before and after methotrexate administration demonstrated a potentiation of corticosteroid hepatotoxicity by the cytostatic. Analysis of methotrexate transporter expression in the liver showed up-regulation of Mrp2, Oatp1a4, and Oat2, and down-regulation of Mrp3. These observations comply with increased biliary excretion and reduced plasma concentrations of their endogenous substrate, conjugated bilirubin. In contrast, single intravenous bolus of dexamethasone did not influence any pharmacokinetic parameter of methotrexate. In conclusion, these results indicate that hepatocellular impairment associated with reduced biliary elimination of methotrexate, and its raised liver content may contribute to increased hepatotoxicity of the drug when co-administered with dexamethasone. Moreover, an influence of dexamethasone on protein expression of anionic drugs transporters in the liver and kidney was demonstrated.
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Simkova 870, 50038 Hradec Kralove, Czech Republic.
authors.forename: Leos
authors.initials: L
authors.lastname: Fuksa
authors.forename: Eva
authors.initials: E
authors.lastname: Brcakova
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kolouchova
authors.forename: Petra
authors.initials: P
authors.lastname: Hirsova
authors.forename: Milos
authors.initials: M
authors.lastname: Hroch
authors.forename: Jolana
authors.initials: J
authors.lastname: Cermanova
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
authors.forename: Stanislav
authors.initials: S
authors.lastname: Micuda
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D001659:Biliary Tract / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008727:Methotrexate / Q000493:pharmacokinetics*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000964:Antimetabolites, Antineoplastic; D026901:Membrane Transport Proteins; D003907:Dexamethasone; D001663:Bilirubin; D008727:Methotrexate