Alterations in P-glycoprotein expression in mouse tissues by doxorubicin: implications for pharmacokinetics in multiple dosing regimens

The purpose of the studies presented here is to determine if alterations in doxorubicin (DOX) pharmacokinetics that seem to occur following multiple-d osing are due to changes in DOX elimination via P-glycoprotein (PGP) mediat ed transport in the liver, kidney and gut. A pharmacokinetic study in femal e Balb/c mice was carried out with blood and tissue DOX levels measured in animals following a single DOX treatment (6 mg/kg), and in animals followin g a second DOX treatment after receiving a DOX treatment a week earlier. Th e pharmacokinetics of DOX in blood and tissues was altered by earlier expos ure to DOX, as the animals that were treated once a week for 2 weeks showed an increased rate of DOX elimination from blood and tissues following the second treatment. Immunoblot analysis of PGP expression in liver and kidney from naive and DOX-treated mice showed an approximately 1.2-fold elevation of PGP protein in these tissues in response to DOX exposure. Immunohistoch emical staining of liver and small intestine sections for PGP showed 1.6-fo ld and 1.9-fold increases, respectively, in the DOX-treated tissues. These results have implications both in multiple-dosing regimens, as well as mult iple-drug regimens, where DOX is used in combination with other drugs that are substrates for PGP-mediated efflux. Increases in PGP expression in both hepatic and extrahepatic tissues can lead to changes in the pharmacokineti cs of DOX, as well as other drugs that are transported by PGP. (C) 2001 Els evier Science Ireland Ltd. All rights reserved.