Plasma and brain pharmacokinetics of letrozole and drug interaction studies with temozolomide in NOD-scid gamma mice and sprague dawley rats
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.
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®.
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.
These results will guide the optimization of dosing regimen for further development of letrozole for HGG treatment.
KeywordsDrug–drug interactions Blood brain barrier Letrozole Temozolomide Pharmacokinetics
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.
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.
- 2.Ostrom QT, Gittleman H, Stetson L, Virk S, Barnholtz-Sloan JS (2018) Epidemiology of intracranial gliomas. Prog Neurol Surg 30:1–11Google Scholar
- 7.Wijaya J, Fukuda Y, Schuetz JD (2017) Obstacles to brain tumor therapy: Key ABC transporters. Int J Mol Sci 18(12): https://doi.org/10.3390/ijms18122544
- 10.Dave N, Sengaonkar V, Chow LML, Kendler A, LaSance K, Desai PB (2015) ATPS-13 Aromatase expression in high grade gliomas: a potential new target for therapy. Neurooncol 17(Suppl 5):v20–v21Google Scholar
- 14.Tivnan A, Heilinger T, Ramsey JM et al (2017) Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells. Oncotarget 8(10):16605–16620CrossRefGoogle Scholar
- 20.Gilant E, Kaza M, Szlagowska A, Serafin-Byczak K, Rudzki PJ (2012) Validated HPLC method for determination of temozolomide in human plasma. Acta Pol Pharm 69(6):1347–1355Google Scholar
- 21.Baker SD, Wirth M, Statkevich P et al (1999) Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. Clin Cancer Res 5(2):309–317Google Scholar
- 23.Liu XD, Xie L, Zhong Y, Li CX (2000) Gender difference in letrozole pharmacokinetics in rats. Acta Pharmacol Sin 21(8):680–684Google Scholar
- 25.Buzdar AU (2003) Pharmacology and pharmacokinetics of the newer generation aromatase inhibitors. Clin Cancer Res 9(1 Pt 2):468S–468S72SGoogle Scholar