| Gemcitabine, a pyrimidine nucleoside anticancer agent clinically used in the treatment of pancreatic cancer, is currently under investigation for the treatment of brain cancer. In cell culture and animal models, gemcitabine has demonstrated efficacy against a broad spectrum of brain neoplasms, while exhibiting little neurotoxicity in patients. Based on this safety and efficacy profile, a few clinical trials are now in progress. However, information pertaining to the central nervous system disposition of gemcitabine is limited, which represents a significant barrier to optimizing its clinical use. In an attempt to overcome this barrier, this study focused on gaining insights into the brain and brain tumoral pharmacokinetics and pharmacodynamics of gemcitabine. We hypothesized that gemcitabine exhibits differential uptake into non-tumor (“normal”) and tumor brain regions and that the uptake is susceptible to modulation by the employed dose, and permeability modulators such as radiation and bradykinin agonist, RMP-7.; We initially employed in vivo microdialysis to investigate the brain pharmacokinetics of gemcitabine employed at 10, 25 and 100 mg/kg doses in rats. The AUCbrain ECF/AUCplasma of gemcitabine was ∼0.1 and both plasma and ECF pharmacokinetics exhibited nonlinear relationship with the employed dose. Most importantly, simultaneous microdialysis of the tumor and non-tumor brain regions of glioma-bearing rats revealed that tumoral AUC of gemcitabine was markedly higher (∼1.8 fold) compared to that of the normal brain, indicating the possibility that the drug may be selectively more cytotoxic to tumor cells. At the levels observed in brain tumoral ECF (0.25–3 μg/ml), gemcitabine exhibited potent cytotoxicity against C6 glioma cells in vitro, which was further enhanced by pre-treatment with ionizing radiation. While radiation (8 Gy) failed to enhance in vivo tumor uptake of gemcitabine, intravenous administration of RMP-7 (3.0, 4.5 and 9.0 μg/kg) selectively increased the tumoral gemcitabine AUC in a dose-related manner (maximal ∼ 2.2-fold). In conclusion, our studies show that at clinically employed doses, brain tumoral concentrations of gemcitabine are considerably higher than those observed in the non-tumor brain and this advantageous differential uptake can be further enhanced by RMP-7, a bradykinin agonist that is undergoing clinical investigation. |
