Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


3250.pdf (18.97 MB)

ETD Abstract Container

Abstract Header

Brain/Brain Tumor Pharmacokinetics and Pharmacodynamics of Letrozole

Dave, Nimita D
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368013158

Abstract Details

2013, PhD, University of Cincinnati, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics.
The lack of well-identified targets and limited access of drugs across the blood-brain and blood- tumor barriers are major impediments to the treatment of brain tumors. In this study, we investigated the potential role of aromatase (CYP19) as a target for the treatment of CNS malignancies, as well as brain disposition and anti-tumor efficacy of letrozole, an aromatase inhibitor, in Sprague Dawley rats. Cytotoxicity and aromatase activity of letrozole against human glioma cell lines were measured using MTT assay and Enzyme Immunoassay respectively. For brain and brain tumor PK of letrozole, rats with and without orthotopic implantation of C6 glioma received letrozole (4 - 12 mg/kg; i.v.). Dual probe intracerebral microdialysis was performed to determine the unbound extracellular fluid (ECF) letrozole concentrations. Serial ECF and blood samples were simultaneously collected over 8 hrs. µ5;PET/CT imaging was performed using 18F FDG to evaluate changes in active tumor volumes pre- and post-treatment of letrozole. Brain tissues were collected at the end of the experiment for histological evaluations. All glioma cell lines included in this study expressed CYP19 and letrozole exerted marked cytotoxicity against these cells ( IC50s 0.1 -3.5 µ5;M). Normal brain ECF and plasma Cmax and AUC0-8hr increased linearly up to 8mg/kg letrozole dose. However, at higher doses, brain and plasma AUC0-8hr increased non-linearly. The relative brain distribution coefficients, measured as the ratio of the observed AUC in ECF and AUC of unbound letrozole in plasma (AUCecf/AUCp, ub) ranged from 0.31 - 0.98. Furthermore, the tumoral ECF levels of letrozole was 1.5 - 2 fold higher relative to tumor-free region of the brain, resulting in tumoral ECF Cmax values that were 10 and 35-fold higher than the observed IC50 value of 0.1 µM against C6 gliomas cells in culture. µPET/CT imaging showed a marked reduction of active tumor volume (≅ 75-90%) after 8-10 days of letrozole treatment (N=7). Thus, employing multifaceted and cutting edge in vitro and in vivo methods, we conclude: a) aromatase is abundantly expressed in glioma cell lines examined, b) letrozole exerts marked cytotoxicity in these cells presumably due to aromatase inhibition, c) letrozole has selectively higher accumulation in tumoral region of the brain and d) In vivo µPET/CT studies show marked efficacy of letrozole on C6 glioma in a preclinical rat model.
Pankaj Desai, Ph.D. (Committee Chair)
Lionel Chow, M.D. Ph.D. (Committee Member)
Gary Gudelsky, Ph.D. (Committee Member)
Xiaoyang Qi, Ph.D. (Committee Member)
Georg Weber, M.D. Ph.D. (Committee Member)
136 p.
Pharmaceuticals
pharmacokinetics; pharmacodynamics; letrozole; brain tumor; preclinical; glioma;

Recommended Citations

Citations

  • Dave, N. D. (2013). Brain/Brain Tumor Pharmacokinetics and Pharmacodynamics of Letrozole [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368013158

    APA Style (7th edition)

  • Dave, Nimita. Brain/Brain Tumor Pharmacokinetics and Pharmacodynamics of Letrozole. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368013158.

    MLA Style (8th edition)

  • Dave, Nimita. "Brain/Brain Tumor Pharmacokinetics and Pharmacodynamics of Letrozole." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368013158

    Chicago Manual of Style (17th edition)

ucin1368013158
346
© , all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.