CNS Penetration of Cyclophosphamide and Metabolites in Mice Bearing Group 3 Medulloblastoma and Non-Tumor Bearing Mice

Authors

  • Olivia Campagne Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis TN.
  • Abigail Davis Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis TN.
  • Bo Zhong Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis TN.
  • Sreenath Nair Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis TN.
  • Victoria Haberman Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis TN.
  • Yogesh T. Patel Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis TN. (currently at Cognigen Corp., Buffalo, NY).
  • Laura Janke Department of Veterinary Pathology Core, St. Jude Children’s Research Hospital, Memphis TN.
  • Martine F. Roussel Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis TN.
  • Clinton Stewart Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis TN. http://orcid.org/0000-0002-1546-9720

DOI:

https://doi.org/10.18433/jpps30608

Abstract

PURPOSE: Cyclophosphamide is widely used to treat children with medulloblastoma; however, little is known about its brain penetration. We performed cerebral microdialysis to characterize the brain penetration of cyclophosphamide (130 mg/kg, IP) and its metabolites [4-hydroxy-cyclophosphamide (4OH-CTX) and carboxyethylphosphoramide mustard (CEPM)] in non-tumor bearing mice and mice bearing orthotopic Group 3 medulloblastoma. METHODS: A plasma pharmacokinetic study was performed in non-tumor-bearing CD1-nude mice, and four cerebral microdialysis studies were performed in non-tumor-bearing (M1 and M3) and tumor-bearing mice (M2 and M4). Plasma samples were collected up to 6-hours post-dose, and extracellular fluid (ECF) samples were collected over 60-minute intervals for 24-hours post-dose. To stabilize and quantify 4OH-CTX, a derivatizing solution was added in blood after collection, and either directly in the microdialysis perfusate (M1 and M2) or in ECF collection tubes (M3 and M4). Plasma/ECF cyclophosphamide and CEPM, and 4OH-CTX concentrations were separately measured using different LC-MS/MS methods. RESULTS: All plasma/ECF concentrations were described using a population-based pharmacokinetic model. Plasma exposures of cyclophosphamide, 4OH-CTX, and CEPM were similar across studies (mean AUC=112.6, 45.6, and 80.8 µmol∙hr/L). Hemorrhage was observed in brain tissue when the derivatizing solution was in perfusate compared with none when in collection tubes, which suggested potential sample contamination in studies M1 and M2. Model-derived unbound ECF to plasma partition coefficients (Kp,uu) were calculated to reflect CNS penetration of the compounds. Lower cyclophosphamide Kp,uu was obtained in tumor-bearing mice versus non-tumor bearing mice (mean 0.15 versus 0.22, p=0.019). No differences in Kp,uu were observed between these groups for 4OH-CTX and CEPM (overall mean 0.10 and 0.07). CONCLUSIONS: Future studies will explore potential mechanisms at the brain-tumor barrier to explain lower cyclophosphamide brain penetration in tumor-bearing mice. These results will be used to further investigate exposure-response relationships in medulloblastoma xenograft models.

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Author Biography

Clinton Stewart, Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis TN.

Department of Pharmaceutical Sciences

Member (Professor)

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Published

2019-12-09

How to Cite

Campagne, O., Davis, A., Zhong, B., Nair, S., Haberman, V., T. Patel, Y., … Stewart, C. (2019). CNS Penetration of Cyclophosphamide and Metabolites in Mice Bearing Group 3 Medulloblastoma and Non-Tumor Bearing Mice. Journal of Pharmacy & Pharmaceutical Sciences, 22(1), 612–629. https://doi.org/10.18433/jpps30608

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Section

Pharmaceutical Sciences; Original Research Articles