Pharmacokinetics of gemcitabine in tumor and non-tumor extracellular fluid of brain: an in vivo assessment in rats employing intracerebral microdialysis.

PURPOSE: Gemcitabine is a pyrimidine nucleoside analogue anticancer agent that has shown promising anti-tumor activity in several experimental models of brain tumor. However, the pharmacokinetic behavior of gemcitabine in the central nervous system, especially in brain tumors is currently not well understood. In this study we evaluated the gemcitabine brain extracellular fluid (ECF) in normal rats and in ECF obtained from tumor- and tumor-free regions of glioma-bearing rats, to better understand the availability of the drug to brain and brain tumors.
METHODS: The brain ECF pharmacokinetics of gemcitabine were investigated employing intracerebral microdialysis following intravenous administration of 10, 25 and 100 mg/kg doses in male Sprague-Dawley rats. In the second phase of the study, gemcitabine (25 mg/kg) was intravenously administered in rats implanted with C6 gliomas and ECF samples were simultaneously obtained from the tumor and tumor-free regions of the brain. Serial blood samples were obtained for evaluating the plasma pharmacokinetics of gemcitabine. Non-compartmental approach was employed for the analyses of the brain ECF and plasma pharmacokinetics of gemcitabine.
RESULTS: Following intravenous administration, gemcitabine rapidly distributed into rat brain. At doses equivalent to 10, 25 and 100 mg/kg, the brain ECF gemcitabine AUC (area under the plasma concentration--time curve measured over the last sampling time point) values were 2.46 +/- 0.7, 3.20 +/- 1.1, and 9.06 +/- 3.0 microg h/ml, respectively. The brain ECF concentrations of gemcitabine declined in parallel with plasma concentrations. At the three doses evaluated, the relative brain distribution coefficient (AUC brainECF/AUC plasma) of gemcitabine ranged from 0.07 to 0.09 suggesting limited gemcitabine availability to brain tissues. Studies on C6 glioma-bearing rats revealed that following an intravenous dose of 25 mg/kg, the AUC values in the tumor-free and tumor-brain regions were 4.52 +/- 2.4, and 9.82 +/- 3.3 microg h/ml, respectively. Thus, the AUC of gemcitabine in the tumor ECF was on average 2.2-fold greater than the corresponding value in the tumor-free ECF of the brain. Plasma pharmacokinetics of gemcitabine remained unaltered in tumor-bearing animals, when compared to plasma pharmacokinetics in healthy animals.
CONCLUSIONS: Our findings suggest that the overall brain exposure to gemcitabine is likely to be low as evident from the relative brain distribution coefficient of <0.1. However, the exposure is likely to be considerably higher in the brain tumor relative to tumor-free regions of the brain. The higher drug levels in brain tumor compared to the non-tumor region may facilitate selectively higher cytotoxicity against brain tumor cells.