Alteration of methotrexate biliary and renal elimination during extrahepatic and intrahepatic cholestasis in rats.
Methotrexate (MTX), an important anticancer and immunosuppressive agent, has been suggested for the treatment of primary biliary cirrhosis. However, the drug's pharmacodynamics and toxicity is dependent on its concentrations in plasma which in turn are directly related to MTX's elimination in the liver and kidney. Therefore, the aim of this study was to evaluate changes in MTX biliary and renal excretion during either intrahepatic or obstructive cholestasis in rats. The steady state pharmacokinetic parameters of MTX were evaluated in rats one (BDO1) or seven (BDO7) days after bile duct obstruction (BDO) or 18 h after administration of lipopolysaccharide (LPS). In comparison to the respective control groups, biliary and total clearances of MTX were decreased to 12% and 49% in the BDO1 group, to 5% and 56% in the BDO7 animals, and to 42% and 43% in the LPS group, respectively. Renal clearance of MTX was unchanged in BDO groups, but decreased to 23% of controls in the LPS animals. The serum biochemistry and expression of main hepatic MTX transporters (Mrp2, Mrp3, Mrp4, Bcrp, Oatp1a1, Oatp1a4 and Oatp1b2) confirmed the pathological cholestatic changes in the liver and partly elucidated the cause of changes in MTX pharmacokinetic parameters. In conclusion, this study is the first describing marked alteration of MTX hepatic and renal elimination induced by cholestasis in rats. Moreover, the reported changes in MTX pharmacokinetics and respective transporter expression suggest important mechanistic differences between the two widely used cholestatic models.
Brcakova
Eva
E
Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University in Prague.
Fuksa
Leos
L
Cermanova
Jolana
J
Kolouchova
Gabriela
G
Hroch
Milos
M
Hirsova
Petra
P
Martinkova
Jirina
J
Staud
Frantisek
F
Micuda
Stanislav
S
D000818:Animals; D001659:Biliary Tract / Q000378:metabolism*; D001692:Biological Transport; D001651:Cholestasis, Extrahepatic / Q000378:metabolism*; D002780:Cholestasis, Intrahepatic / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008727:Methotrexate / Q000493:pharmacokinetics*; D023421:Models, Animal; D051381:Rats; D017208:Rats, Wistar
D008070:Lipopolysaccharides; D026901:Membrane Transport Proteins; D008727:Methotrexate