MODULATION OF DOXORUBICIN CONCENTRATION BY CYCLOSPORINE-A IN BRAIN AND TESTICULAR BARRIER TISSUES EXPRESSING P-GLYCOPROTEIN IN RATS

P-glycoprotein (Pgp) is an inducible transmembrane protein that functi ons as an ATP-dependent efflux pump. Pgp is normally expressed in two types of cells: specialized epithelial cells with secretory/excretory functions (e.g., proximal renal tubules) and specialized endotheiial c ells (e.g., the capillary endothelial cells of the blood-brain barrier ). In normal tissues, Pgp could exert a cytoprotective effect by facil itating excretion of drugs. It follows that inhibition of Pgp would al ter the pharmacokinetics of drugs, like doxorubicin, in cells that exp ress Pgp. The purpose of this study was to determine whether or not in hibition of Pgp by cyclosporin A (CsA) facilitated the transport of ce rtain drugs across the blood tissue barriers of the brain and testes ( barriers tissues expressing Pgp). 120 retired male breeder CD Fisher r ats were randomly assigned to groups of 4 rats each. They were given e ither CsA, CsA vehicle, or saline followed by doxorubicin (Dox), cispl atin (CDDP), Evan's blue (EB), sodium fluorescein (NaF), or horseradis h peroxidase (HRP). There was a CsA dose dependent increase in the tis sue concentration of doxorubicin in brain and testes, but platinum (Pt ) concentrations, derived from CDDP, were unaffected. Unlike CDDP, Dox : can be effluxed by Pgp. These increases in Dox concentrations were n ot due to altered vascular permeability as a result of CsA treatment a s determined by lack of EB, NaF, or HRP in brain parenchyma. Modulatio n of Pgp function may prove to be useful for improving chemotherapy ef ficacy for patients with malignancies affecting tissues with blood-tis sue barriers.