PURPOSE: Cyclosporine A (CyA) is able to inhibit P-glycoprotein (P-gp) and to increase cytotoxicity of some anticancer drugs, including etoposide. However, the effect of CyA on the distribution of etoposide in normal tissues, which could affect their toxicity, has not been studied extensively. The purpose of this study was to investigate the effect of CyA on the pharmacokinetics and tissue distribution of etoposide in rats. METHODS: Etoposide was administered as an i.v. bolus injection (3 mg) or as a constant-rate i.v. infusion (8 mg/h) 1 h after the beginning of infusion of CyA or saline. Animals were killed 1 h after the bolus administration or after the beginning of infusion of etoposide, and plasma and tissue (testicle, muscle, heart, lung, spleen, kidney, liver, colon, and intestine) concentrations of etoposide, blood concentrations of CyA were determined. All analyses were performed by HPLC. RESULTS: Infusion of CyA (1 mg/h) in rats treated with an i.v. bolus of etoposide caused a decrease in the plasma clearance (5.4+/-2.1 vs 9.3+/-2.4 ml/min), and an increase in plasma and tissue concentrations of etoposide, but the tissue-to-plasma concentration ratios of etoposide were not affected. When etoposide was infused at a constant rate to reach a steady-state plasma level, coinfusion of CyA (10 mg/h) also caused a decrease in the plasma clearance (4.8+/-1.5 vs 9.8+/-4.7 ml/min), and an increase in plasma and tissue concentrations of etoposide. Only lung and spleen showed tissue-to-plasma ratios of etoposide significantly higher than obtained in rats coinfused with saline, but the differences were small. CONCLUSIONS: The higher tissue concentrations of etoposide caused by CyA administration were mainly a direct consequence of the higher plasma concentration resulting from a decrease in the clearance of etoposide rather than a consequence of changes in the tissue distribution of etoposide. Extrapolation of the results obtained in rats to clinical practice suggests that the coadministration of etoposide and CyA would not lead to an increase in the toxicity of etoposide if the dose were decreased in the same proportion as clearance of etoposide is decreased by CyA administration.
PURPOSE:Cyclosporine A (CyA) is able to inhibit P-glycoprotein (P-gp) and to increase cytotoxicity of some anticancer drugs, including etoposide. However, the effect of CyA on the distribution of etoposide in normal tissues, which could affect their toxicity, has not been studied extensively. The purpose of this study was to investigate the effect of CyA on the pharmacokinetics and tissue distribution of etoposide in rats. METHODS:Etoposide was administered as an i.v. bolus injection (3 mg) or as a constant-rate i.v. infusion (8 mg/h) 1 h after the beginning of infusion of CyA or saline. Animals were killed 1 h after the bolus administration or after the beginning of infusion of etoposide, and plasma and tissue (testicle, muscle, heart, lung, spleen, kidney, liver, colon, and intestine) concentrations of etoposide, blood concentrations of CyA were determined. All analyses were performed by HPLC. RESULTS: Infusion of CyA (1 mg/h) in rats treated with an i.v. bolus of etoposide caused a decrease in the plasma clearance (5.4+/-2.1 vs 9.3+/-2.4 ml/min), and an increase in plasma and tissue concentrations of etoposide, but the tissue-to-plasma concentration ratios of etoposide were not affected. When etoposide was infused at a constant rate to reach a steady-state plasma level, coinfusion of CyA (10 mg/h) also caused a decrease in the plasma clearance (4.8+/-1.5 vs 9.8+/-4.7 ml/min), and an increase in plasma and tissue concentrations of etoposide. Only lung and spleen showed tissue-to-plasma ratios of etoposide significantly higher than obtained in rats coinfused with saline, but the differences were small. CONCLUSIONS: The higher tissue concentrations of etoposide caused by CyA administration were mainly a direct consequence of the higher plasma concentration resulting from a decrease in the clearance of etoposide rather than a consequence of changes in the tissue distribution of etoposide. Extrapolation of the results obtained in rats to clinical practice suggests that the coadministration of etoposide and CyA would not lead to an increase in the toxicity of etoposide if the dose were decreased in the same proportion as clearance of etoposide is decreased by CyA administration.