MODULATION EFFECTS OF CYCLOSPORINE ON ETOPOSIDE PHARMACOKINETICS AND CNS DISTRIBUTION IN THE RAT UTILIZING MICRODIALYSIS

In the present study, we evaluated the pharmacokinetics of the chemoth erapeutic agent etoposide (ET) under steady-state conditions and exami ned its extent of distribution into the CNS of conscious animals. An i .v. infusion of 15 mg/kg/hr was administered to nine rats. Each of the nine rats also received the potent multidrug resistance (MDR) modulat or cyclosporine (CSA). Upon the addition of CSA, the i.v. treated anim als demonstrated a 53% decrease in ET clearance. This decrease resulte d in a greater than 2-fold increase in the steady-state concentrations of ET. The corrected brain-blood ratio (BBR(corr)) was 0.36 +/- 0.18 prior to CSA treatment, and although CNS concentrations increased upon the addition of CSA, there was no increase in the BBR(corr) (0.24 +/- 0.10). The present study demonstrates that the increase of ET in the CNS following CSA is a result of a decrease in ET systemic clearance a nd not an inhibition of ET efflux from the CNS.