Abstract 3360: The pharmacokinetics of letrozole in brain and brain tumor in rats (orthotopically implanted C6 glioma) assessed using microdialysis.
Authors: Dave Nimita , Qi Xiaoyang , Gudelsky Gary G. , Desai Pankaj B. 
Published: August 2014

The presence of blood-brain or blood-tumor barrier is well known to restrict access of drugs to CNS malignancies. For most drugs, there is limited quantitative information pertaining to the time course of drug absorption, distribution and elimination and the resulting drug exposure. In this study, we employed intracerebral microdialysis to access the extracellular fluid (ECF) to assess the pharmacokinetics of letrozole in brain and primary glioma in rats. Intracerebral microdialysis (perfusion rate; 2 μl/min) was performed in female rats to determine the unbound letrozole ECF concentrations. Serial ECF samples were collected over a 30 min period up to 8 hrs following drug administration. Blood samples were simultaneously collected through the jugular vein cannulation. Letrozole concentrations in extracted plasma and dialysate samples were analyzed employing HPLC. In vivo relative recovery was estimated to be 9.5%. Normal brain versus plasma pharmacokinetic study employed four doses (4, 6, 8 & 12 mg/kg; i.v.). For tumoral pharmacokinetic studies, C6 glioma cells were orthotopically implanted in the right striatum while the left hemisphere served as control. Ten days after tumor implantation, dual probe microdialysis was performed under the aforementioned experimental conditions following letrozole administration at 4 and 8 mg/kg doses. Pharmacokinetic analyses were carried out using WinNonlin 6.2 (Pharsight Inc., CA). Normal brain ECF and plasma peak concentrations (Cmax) and the Area Under the Curve (AUC0-8hr) increased linearly with increase in doses of letrozole administration up to 8mg/kg dose. However, at higher dose of 12mg/kg brain and plasma AUC0-8hr increased non-linearly. The relative brain distribution coefficient, calculated as (AUCbrain ecf/AUCplasma), was 0.122 at the lowest dose of 4mg/kg letrozole, whereas, 0.3 for the other three doses. The distribution of letrozole into the brain was rapid with the time to attain the peak levels (Tmax) ranging between 1.3-1.5 hr for the four doses. Furthermore, the tumoral uptake of letrozole was 1.5 - 2 folds higher relative to tumor-free region of the brain for the two doses of letrozole, 4 and 8 mg/kg. Histological evaluation confirmed the presence and restriction of glioma in the right hemisphere, and the passage of the microdialysis probe in the tumor mass. Our extensive in vivo pharmacokinetic study represents the first quantitative assessment of letrozole exposure to the brain and brain tumor tissues. These studies clearly demonstrate a rapid and high partitioning of letrozole to the brain with higher accumulation in the tumoral region of the brain. Further pharmacokinetic and pharmacodynamics modeling and simulations of the observed unbound ECF concentrations are in progress to assess clinical implications of our findings.

Citation Format: Nimita Dave, Xiaoyang Qi, Gary G. Gudelsky, Pankaj B. Desai. The pharmacokinetics of letrozole in brain and brain tumor in rats (orthotopically implanted C6 glioma) assessed using microdialysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3360. doi:10.1158/1538-7445.AM2013-3360