title: Modulation effects of cyclosporine on etoposide pharmacokinetics and CNS distribution in the rat utilizing microdialysis.
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.
authors.affiliation: College of Pharmacy, Department of Medicine, University of Kentucky, Lexington, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Burgio
authors.forename: M P
authors.initials: MP
authors.lastname: Gosland
authors.forename: P J
authors.initials: PJ
authors.lastname: McNamara
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D005047:Etoposide / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D008297:Male; D017551:Microdialysis; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005047:Etoposide; D016572:Cyclosporine