Stacy S Shord1, Joseph R Camp, Lucy A F Young. 1. University of Illinois at Chicago, College of Pharmacy (M/C 886), Chicago, Illinois 60612, USA. sshord@uic.edu
Abstract
BACKGROUND: We identified a drug-drug interaction between gemcitabine and paclitaxel in a clinical pharmacokinetic study. The purpose of the present study was to determine whether paclitaxel affected the uptake and accumulation of the parent drug gemcitabine and the formation of its metabolites after treatment of cells with gemcitabine in vitro. MATERIALS AND METHODS: The human leukemia cell line CEM was treated with 15 micoM 3H-gemcitabine, with and without paclitaxel, and the accumulation of radiolabeled gemcitabine was assessed up to one minute and one hour. Peripheral blood mononuclear cells (PMN) and hepatocytes were treated with gemcitabine, with or without paclitaxel, for specified amounts of time at three concentrations of gemcitabine, and the concentrations of gemcitabine and its metabolites were measured by liquid chromatography. RESULTS: In CEM cells, paclitaxel reduced the uptake and accumulation of gemctabine by 32% and 30%, respectively. In the hepatocytes, the mean concentrations of gemcitabine increased in the cell culture media 100%, 48% and 38% when treated with paclitaxel plus gemcitabine 5, 15 and 30 microM, respectively, compared to gemcitabine alone. The concentrations of the deaminated metabolite dFdU were significantly decreased in the cell culture media. In the PMN, the intracellular accumulation of active triphosphorylated metabolite dFdCTP was lower in cells treated with paclitaxel (up to 83%) compared to the control. CONCLUSION: Paclitaxel substantially reduced the uptake and accumulation of gemcitabine and the formation of its metabolites in vitro at clinically relevant concentrations.
BACKGROUND: We identified a drug-drug interaction between gemcitabine and paclitaxel in a clinical pharmacokinetic study. The purpose of the present study was to determine whether paclitaxel affected the uptake and accumulation of the parent drug gemcitabine and the formation of its metabolites after treatment of cells with gemcitabine in vitro. MATERIALS AND METHODS: The humanleukemia cell line CEM was treated with 15 micoM 3H-gemcitabine, with and without paclitaxel, and the accumulation of radiolabeled gemcitabine was assessed up to one minute and one hour. Peripheral blood mononuclear cells (PMN) and hepatocytes were treated with gemcitabine, with or without paclitaxel, for specified amounts of time at three concentrations of gemcitabine, and the concentrations of gemcitabine and its metabolites were measured by liquid chromatography. RESULTS: In CEM cells, paclitaxel reduced the uptake and accumulation of gemctabine by 32% and 30%, respectively. In the hepatocytes, the mean concentrations of gemcitabine increased in the cell culture media 100%, 48% and 38% when treated with paclitaxel plus gemcitabine 5, 15 and 30 microM, respectively, compared to gemcitabine alone. The concentrations of the deaminated metabolite dFdU were significantly decreased in the cell culture media. In the PMN, the intracellular accumulation of active triphosphorylated metabolite dFdCTP was lower in cells treated with paclitaxel (up to 83%) compared to the control. CONCLUSION:Paclitaxel substantially reduced the uptake and accumulation of gemcitabine and the formation of its metabolites in vitro at clinically relevant concentrations.