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.
Footnotes
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Send reprint requests to: Dr. Patrick J. McNamara, Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, 433 College of Pharmacy Building, University of Kentucky, Lexington, KY 40536-0082. E-mail: pmcnamar{at}pop.uky.edu
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↵1 This work was supported, in part by the University of Kentucky Dissertation Year Fellowship (D.E.B.) and a University of Kentucky Medical Center Research Grant (P.J.M.).
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↵2 Present address: Quintiles, Inc., P.O. Box 13979, Research Triangle Park, NC 27709.
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↵3 Correspondence to Dr. Patrick J. McNamara, Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, 433 College of Pharmacy Building, University of Kentucky, Lexington, KY 40536-0082. E-mail: pmcnamar{at}pop.uky.edu
- Abbreviations:
- BBB
- blood-brain barrier
- CNS
- central nervous system
- Received May 13, 1997.
- Accepted July 23, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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