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Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 1, pp 81–89 | Cite as

Plasma and brain pharmacokinetics of letrozole and drug interaction studies with temozolomide in NOD-scid gamma mice and sprague dawley rats

  • Priyanka Arora
  • Courtney Huff Adams
  • Gary Gudelsky
  • Biplab DasGupta
  • Pankaj B. DesaiEmail author
Original Article

Abstract

Purpose

The aromatase inhibitor, letrozole, is being investigated in experimental animal models as a novel treatment for high-grade gliomas (HGGs). To facilitate optimal dosing for such studies, we evaluated the plasma and brain pharmacokinetics (PK) of letrozole in NOD-scid gamma (NSG) mice, which are frequently employed for assessing efficacy against patient-derived tumor cells. Furthermore, we evaluated the potential PK interactions between letrozole and temozolomide (TMZ) in Sprague–Dawley rats.

Methods

NSG mice were administered letrozole (8 mg/kg; i.p) as a single or multiple dose (b.i.d, 10 days). Brain tissue and blood samples were collected over 24 h. Letrozole and TMZ interaction study employed jugular vein-cannulated rats (three groups; TMZ alone, letrozole alone and TMZ + letrozole). Intracerebral microdialysis was performed for brain extracellular fluid (ECF) collection simultaneously with venous blood sampling. Drug levels were measured employing HPLC and PK analysis was conducted using Phoenix WinNonlin®.

Results

In NSG mice, peak plasma and brain tissue letrozole concentrations (Cmax) were 3–4 and 0.8–0.9 µg/ml, respectively. The elimination half-life was 2.6 h with minimal accumulation following multiple dosing. In the drug interaction study, no PK changes were evident when TMZ and letrozole were given in combination. For instance, peak plasma and brain ECF TMZ levels when given alone were 14.7 ± 1.1 and 4.6 ± 0.6 µg/ml, respectively, and 12.6 ± 2.4 and 3.4 ± 0.8 µg/ml, respectively, when given with letrozole.

Conclusions

These results will guide the optimization of dosing regimen for further development of letrozole for HGG treatment.

Keywords

Drug–drug interactions Blood brain barrier Letrozole Temozolomide Pharmacokinetics 

Notes

Acknowledgements

The study was supported by grants from the University of Cincinnati Brain Tumor Center Molecular Therapeutics Program, Neuroscience Institute and Technology Commercialization Accelerator.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All the experiments were conducted in strict accordance with the Institutional Animal Care and Use Committee (IACUC)-approved protocols of Cincinnati Children’s Hospital Medical Center (CCHMC) and University of Cincinnati and were performed as per the highest international standards of animal welfare outlined by the NIH’s Guide for the Care and Use of Laboratory Animals.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Pharmaceutical Sciences, College of Pharmacy, James L. Winkle College of PharmacyUniversity of CincinnatiCincinnatiUSA
  2. 2.Division of OncologyCincinnati Children’s Hospital Medical CenterCincinnatiUSA

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