Alteration of methotrexate biliary and renal elimination during extrahepatic and intrahepatic cholestasis in rats

Abstrakt

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.

The aim of the present study was to describe changes in the pharmacokinetics of MTX during either obstructive or intrahepatic cholestasis in rats. A detailed clearance study of MTX was performed using the in vivo rat model of both intrahepatic and extrahepatic cholestasis.

Reported changes in MTX pharmacokinetics and respective transporter expression suggest important mechanistic differences between the two widely used cholestatic models. Finally, although we are aware about limits of our animal models for prediction of clinical behavior of the drug, based on results of kinetic studies presented herein, increased accumulation of MTX might be expected in patients with cholestasis.