Abstract

In this study, P-glycoprotein modulator effects on pharmacokinetics and central nervous system distribution of the chemotherapeutic agent etoposide were evaluated. The multidrug resistance transporter P-glycoprotein is expressed in normal tissues, and its physiological function is thought to be an excretory and/or protective one. To examine this further, we evaluated etoposide under steady-state and bolus dose conditions. In microdialysis infusion studies, etoposide 15 mg/kg/hr was administered to 12 rats. Rats received sodium cyanide (1 or 100 mM), trifluoperazine (30 mM) or cyclosporine (4.14 mM)via microdialysis probe at 3.5 hr after etoposide infusion initiation. High-dose sodium cyanide (100 mM) increased the etoposide BBR,_corr from 0.09 ± 0.03 to 0.85 ± 0.35. Similarly, trifluoperazine significantly increased the BBR,_corr (0.05 ± 0.02 vs. 1.30 ± 0.43), whereas cyclosporine had no effect. In bolus studies, etoposide (10–12 mg/kg) was given alone or concomitant to cyclosporine (5 mg/kg) or tamoxifen (13.5 mg/kg). Control etoposide total systemic clearance (ml/min/kg) was 29.3 ± 13.0 vs. 16.0 ± 1.9 and 22.6 ± 5.3 for cyclosporine and tamoxifen treatments, respectively. Etoposide nonrenal clearance (ml/min/kg) values for cyclosporine (12.0 ± 1.6) and tamoxifen (18.1 ± 3.6) treatments was also decreased from controls (23.5 ± 10.5). Etoposide renal clearance (ml/min/kg) values (5.7 ± 2.5) were not significantly different from cyclosporine (4.0 ± 0.7) or tamoxifen (4.6 ± 1.7) treatments, respectively. In this study, the ability of sodium cyanide and trifluoperazine to alter etoposide BBR,_corr, demonstrated that etoposide distribution into brain is partly controlled by an active transport process. Similarly, the results indicate cyclosporine inhibits etoposide transport at the canalicular membrane and/or etoposide P-450 metabolism.