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Modulation effects of cyclosporine on etoposide pharmacokinetics and CNS distribution in the rat utilizing
D E Burgio1, M P Gosland, P J McNamara
1College of Pharmacy, Department of Medicine, University of Kentucky, Lexington, USA.
Abstract:
In the present study, we evaluated the pharmacokinetics of the chemotherapeutic agent etoposide (ET) under steady-state conditions and examined 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) modulator cyclosporine (CSA). Upon the addition of CSA, the i.v. treated animals demonstrated a 53% decrease in ET clearance. This decrease resulted 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 and not an inhibition of ET efflux from the CNS.
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