Skip to main content

Advertisement

SpringerLink
Log in

The pharmacokinetics of letrozole in brain and brain tumor in rats with orthotopically implanted C6 glioma, assessed using intracerebral microdialysis

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Emerging evidence suggests that primary and metastatic brain tumors may be sensitive to hormonal manipulations. However, the pharmacokinetics of compounds against such targets in the brain and, more importantly, in the brain tumor are not well characterized. Here, we investigated the pharmacokinetics of letrozole, a third-generation aromatase inhibitor, in the normal brain and in orthotopically implanted C6 glioma in Sprague–Dawley rats.

Methods

Intracerebral microdialysis was employed to determine the concentrations of unbound letrozole in the brain extracellular fluid (ECF) while simultaneously collecting blood samples (via jugular vein) to assess plasma levels of letrozole. Letrozole was administered intravenously at doses of 4, 6, 8 and 12 mg/kg, and ECF and blood samples were collected over 8 h. For assessing normal versus tumoral brain pharmacokinetics, letrozole (4 or 8 mg/Kg; i.v.) was administered 10 days after implantation of C6 glioma in the brain. Dual-probe intracerebral microdialysis was employed for assessing ECF samples from tumor-free and tumor-bearing regions of the brain.

Results

Normal brain ECF and plasma C max and AUC0–8h increased linearly with letrozole doses up to 8 mg/kg dose, but at 12 mg/kg, the pharmacokinetics were nonlinear. The relative brain distribution coefficients, AUCECF/AUCplasma (ub), were 0.3–0.98. The tumoral uptake of letrozole was 1.5- to 2-fold higher relative to tumor-free region.

Conclusions

Thus, letrozole permeability across the blood brain barrier is high, and the exposure to the brain is dose dependent. Furthermore, the brain tumoral letrozole levels are markedly higher than those in the tumor-free regions, which underscore potential selectivity of its activity against tumor cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ballabh P, Braun A, Nedergaard M (2004) The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16:1–13

    Article  PubMed  CAS  Google Scholar 

  2. Wagner LE 2nd, Eaton M, Sabnis SS, Gingrich KJ (1999) Meperidine and lidocaine block of recombinant voltage-dependent Na + channels: evidence that meperidine is a local anesthetic. Anesthesiology 91(5):1481–1490

    Article  PubMed  CAS  Google Scholar 

  3. Leibenr S, Fischmann A, Rascher G, Duffner F, Kalbacher H, Wolburg H (2000) Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol 100(3):323–331

    Article  Google Scholar 

  4. Shibata S (1989) Ultrastructure of capillary walls in human brain tumors. Acta Neutopathol 78(8):561–571

    Article  CAS  Google Scholar 

  5. Blasberg R, Horowitz M, Molnar P, Strong J, Kornblith P, Pleasants R, Fenstermacher J (1983) Regional [14C]misonidazole distribution in experimental RT-9 brain tumors. Cancer Res 43(8):3800–3807

    PubMed  Google Scholar 

  6. Ostrowitzki S, Fick J, Roberts TP, Wendland MF, Aldape KD, Mann JS, Israel MA, Brasch RC (1998) Comparison of gadopentetate dimeglumine and albumin(Gd-DTPA)30 for microvessel characterization in an intracranial glioma model. J Magn Reson Imaging 8(4):799–806

    Article  PubMed  CAS  Google Scholar 

  7. Nakagawa H, Groothuis DR, Owens ES, Fenstermacher JD, Patlak CS, Blasberg RG (1987) Dexamethasone effects on [125I]albumin distribution in experimental RG-2 gliomas and adjacent brain. J Cereb Blood Flow Metab 7(6):687–701

    Article  PubMed  CAS  Google Scholar 

  8. Schlageter KE, Molnar P, Lapin GD, Groothuis DR (1999) Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties. Microvasc Res 58(3):312–328

    Article  PubMed  CAS  Google Scholar 

  9. Regina A, Demeule M, Laplante A, Jodoin J, Dagenais C, Berthelet F, Moghrabi A, Bellveau R (2001) Multidrug resistance in brain tumors: roles of the blood-brain barrier. Cancer Metastasis Rev 20(1–2):13–25

    Article  PubMed  CAS  Google Scholar 

  10. Toth K, Vaughan MM, Peress NS, Slocum HK, Rustum YM (1996) MDR-1 P-glycoprotein is expressed by endothelial cells of newly formed capillaries in human gliomas but is not expressed in the neovasculature of other primary tumors. Am J Pathol 149(3):853–858

    PubMed  CAS  Google Scholar 

  11. Patel S, DiBiase S, Meisenberg B, Flannery T, Patel A, Dhople A, Cheston S, Amin P (2012) Phase I clinical trial assessing temozolomide and tamoxifen with concomitant radiotherapy for treatment of high-grade glioma. Int J Radiat Oncol Biol Phys 82:739–742

    Article  PubMed  CAS  Google Scholar 

  12. Vertosick FT Jr, Selker RG, Randall MS, Kristofik MP, Rehn T (1994) A comparison of the relative chemosensitivity of human gliomas to tamoxifen and n-desmethyltamoxifen in vitro. J Neurooncol 19:97–103

    Article  PubMed  Google Scholar 

  13. Madhup R, Kirti S, Bhatt ML, Srivastava PK, Srivastava M, Kumar S (2006) Letrozole for brain and scalp metastases from breast cancer–a case report. Breast 15:440–442

    Article  PubMed  CAS  Google Scholar 

  14. Ito K et al (2009) A case of brain metastases from breast cancer that responded to anastrozole monotherapy. Breast J 15:435–437

    Article  PubMed  Google Scholar 

  15. Dellapasqua S, Colleoni M (2010) Letrozole. Expert Opin Drug Metab Toxicol 6:251–259

    Article  PubMed  CAS  Google Scholar 

  16. Lonning P (2003) Clinical pharmacokinetics of aromatase inhibitors and inactivators. Clin Pharmacokinet 42:619–631

    Article  PubMed  CAS  Google Scholar 

  17. Lonning P, Pfister C, Martoni A, Zamagni C (2003) Pharmacokinetics of third-generation aromatase inhibitors. Semin Oncol 30:23–32

    Article  PubMed  CAS  Google Scholar 

  18. Kil KE, Biegon A, Ding YS, Fischer A, Ferrieri RA, Kim SW, Pareto D, Schueller MJ, Fowler JS (2009) Synthesis and PET studies of [(11)C-cyano]letrozole (Femara), an aromatase inhibitor drug. Nucl Med Biol 36:215–223

    Article  PubMed  CAS  Google Scholar 

  19. Benveniste H, Huttemeier PC (1990) Microdialysis–theory and application. Prog Neurobiol 35:195–215

    Article  PubMed  CAS  Google Scholar 

  20. Yamamoto BK, Pehek EA (1990) A neurochemical heterogeneity of the rat striatum as measured by in vivo electrochemistry and microdialysis. Brain Res 506:236–242

    Article  PubMed  CAS  Google Scholar 

  21. Workman P, Balmain A, Hickman JA, McNally NJ, Rohas AM, Mitchison NA, Pierrepoint CG, Raymond R, Rowlatt C, Stephens TC et al (1988) UKCCCR guidelines for the welfare of animals in experimental neoplasia. Lab Anim 22:195–201

    Article  PubMed  CAS  Google Scholar 

  22. Paxinos G, Watson CR, Emson PC (1980) Ache-stained horizontal sections of the rat brain in stereotaxic coordinates. J Neurosci Methods 3(2):129–149

    Article  PubMed  CAS  Google Scholar 

  23. Lee KJ, Mower R, Hollenbeck T, Castelo J, Johnson N, Gordon P, Sinko PJ, Holme K, Lee YH (2003) Modulation of nonspecific binding in ultrafiltration protein binding studies. Pharm Res 20:1015–1021

    Article  PubMed  CAS  Google Scholar 

  24. Apparaju SK, Gudelsky GA, Desai PB (2008) Pharmacokinetics of gemcitabine in tumor and non-tumor extracellular fluid of brain: an in vivo assessment in rats employing intracerebral microdialysis. Cancer Chemother Pharmacol 61(2):223–229

    Article  PubMed  CAS  Google Scholar 

  25. Silvera SA, Miller AB, Rohan TE (2006) Hormonal and reproductive factors and risk of glioma: a prospective cohort study. Int J Cancer 118:1321–1324

    Article  PubMed  CAS  Google Scholar 

  26. Kabat GC, Etgen AM, Rohan TE (2010) Do steroid hormones play a role in the etiology of glioma? Cancer Epidemiol Biomarkers Prev 19:2421–2427

    Article  PubMed  CAS  Google Scholar 

  27. Kabat GC, Park Y, Hollenbeck AR, Schatzkin A, Rohan TE (2011) Reproductive factors and exogenous hormone use and risk of adult glioma in women in the NIH-AARP diet and health study. Int J Cancer 128:944–950

    Article  PubMed  CAS  Google Scholar 

  28. Huang K, Whelan EA, Ruder AM, Ward EM, Deddens JA, Davis-King KE, Carreon T, Waters MA, Butler MA, Calvert GM et al (2004) Reproductive factors and risk of glioma in women. Cancer Epidemiol Biomarkers Prev 13:1583–1588

    PubMed  Google Scholar 

  29. Cicuttini FM, Hurley SF, Forbes A, Donnan GA, Salzberg M, Giles GG, McNeil JJ (1997) Association of adult glioma with medical conditions, family and reproductive history. Int J Cancer 71:203–207

    Article  PubMed  CAS  Google Scholar 

  30. Berny W, Weiser A, Jarmundowicz W, Markowska-Woyciechowska A, Zaluski R, Zub W (2004) Analysis of expression of estrogen (ER) and progesterone receptors (PR) in brain glial tumors and its correlation with expression of p53 protein and proliferating cell nuclear antigen (PCNA)]. Neurol Neurochir Pol 38:367–371

    PubMed  Google Scholar 

  31. Fujimoto M, Yoshino E, Hirakawa K, Fujimoto J, Tamaya T (1984) Estrogen receptors in brain tumors. Clin Neuropharmacol 7:357–362

    Article  PubMed  CAS  Google Scholar 

  32. Sun KH (1989) Estrogen receptors in patients with brain tumors. Zhonghua Wai Ke Za Zhi 27(299–300):318

    Google Scholar 

  33. Walker MC, Tong X, Perry T, Alavijeh MS, Patsalos PN (2000) Comparison of serum, cerebrospinal fluid and brain extracellular fluid pharmacokinetics of lamotrigine. Brit J Pharmcol 130:242–248

    Article  CAS  Google Scholar 

  34. de Lange ECM, Danhof M (2002) Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting. Clin Pharmacokinet 41(10):691–703

    Article  PubMed  Google Scholar 

  35. Elmquist WF, Sawchuk RJ (1997) Application of microdialysis in pharmacokinetic studies. Pharm Res 14:267–288

    Article  PubMed  CAS  Google Scholar 

  36. Chaurasia CS, Muller M, Bashaw ED, Benfeldt E, Bolinder J, Bullock R, Bungay PM, DeLange EC, Derendorf H, Elmquist WF et al (2007) AAPS-FDA workshop white paper: microdialysis principles, application and regulatory perspectives. Pharm Res 24:1014–1025

    Article  PubMed  CAS  Google Scholar 

  37. Blakeley J, Portnow J (2010) Microdialysis for assessing intratumoral drug disposition in brain cancers: a tool for rational drug development. Expert Opin Drug Metab Toxicol 6:1477–1491

    Article  PubMed  CAS  Google Scholar 

  38. Liu XD, Xie L, Zhong Y, Li CX (2000) Gender differences in letrozole pharmacokinetics in rats. Acta Pharmacol Sin 21(8):680–684

    PubMed  CAS  Google Scholar 

  39. Pfister CU, Martoni A, Zamagni C, Lelli G, De Braud F, Souppart C, Duval M, Hornberger U (2001) Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara) in breast cancer patients. Biopharm Drug Dispos 22:191–197

    Article  PubMed  CAS  Google Scholar 

  40. Grobben B, De Deyn PP, Slegers H (2002) Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion. Cell Tissue Res 310:257–270

    Article  PubMed  CAS  Google Scholar 

  41. Devineni D, Klein-Szanto A, Gallo JM (1996) In vivo microdialysis to characterize drug transport in brain tumors: analysis of methotrexate uptake in rat glioma-2 (RG-2)-bearing rats. Cancer Chemother Pharmacol 38(6):499–507

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA

    Nimita Dave, Gary A. Gudelsky & Pankaj B. Desai

Authors
  1. Nimita Dave
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gary A. Gudelsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pankaj B. Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pankaj B. Desai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dave, N., Gudelsky, G.A. & Desai, P.B. The pharmacokinetics of letrozole in brain and brain tumor in rats with orthotopically implanted C6 glioma, assessed using intracerebral microdialysis. Cancer Chemother Pharmacol 72, 349–357 (2013). https://doi.org/10.1007/s00280-013-2205-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-013-2205-y

Keywords

Search

Navigation