TY - JOUR
T1 - Dexamethasone reduces methotrexate biliary elimination and potentiates its hepatotoxicity in rats
AU - Fuksa, Leos
AU - Brcakova, Eva
AU - Kolouchova, Gabriela
AU - Hirsova, Petra
AU - Hroch, Milos
AU - Cermanova, Jolana
AU - Staud, Frantisek
AU - Micuda, Stanislav
N1 - Funding Information:
We gratefully acknowledge the skilful technical assistance of Jitka Hajkova, and Hana Krupickova. This study was supported by grants from the Ministry of Education of the Czech Republic Nos. OC09072 and MSM 0021620820.
PY - 2010/1/12
Y1 - 2010/1/12
N2 - 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.
AB - 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.
KW - Biliary excretion
KW - Conjugated bilirubin
KW - Dexamethasone
KW - Drug transporters
KW - Methotrexate
UR - http://www.scopus.com/inward/record.url?scp=71849102008&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=71849102008&partnerID=8YFLogxK
U2 - 10.1016/j.tox.2009.11.010
DO - 10.1016/j.tox.2009.11.010
M3 - Article
C2 - 19922765
AN - SCOPUS:71849102008
SN - 0300-483X
VL - 267
SP - 165
EP - 171
JO - Toxicology
JF - Toxicology
IS - 1-3
ER -