title: Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model.
abstract: OBJECTIVE
  Mebendazole (MBZ), first used as an antiparasitic drug, shows preclinical efficacy in models of glioblastoma and medulloblastoma. Three different mebendazole polymorphs (A, B, and C) exist, and a detailed assessment of the brain penetration, pharmacokinetics, and antitumor properties of each individual mebendazole polymorph is necessary to improve mebendazole-based brain cancer therapy.
  
  
  RESULTS
  In this study, various marketed and custom-formulated mebendazole tablets were analyzed for their polymorph content by IR spectroscopy and subsequently tested in an orthotopic GL261 mouse glioma model for efficacy and tolerability. The pharmacokinetics and brain concentration of mebendazole polymorphs and two main metabolites were analyzed by LC/MS. We found that polymorph B and C both increased survival in a GL261 glioma model, as B exhibited greater toxicity. Polymorph A showed no benefit. Polymorph B and C both reached concentrations in the brain that exceeded the IC₅₀ in GL261 cells 29-fold. In addition, polymorph C demonstrated an AUC₀₋₂₄h brain-to-plasma (B/P) ratio of 0.82, whereas B showed higher plasma AUC and lower B/P ratio. In contrast, polymorph A presented markedly lower levels in the plasma and brain. Furthermore, the combination with elacridar was able to significantly improve the efficacy of polymorph C in GL261 glioma and D425 medulloblastoma models in mice.
  
  
  CONCLUSIONS
  Among mebendazole polymorphs, C reaches therapeutically effective concentrations in the brain tissue and tumor with fewer side effects, and is the better choice for brain cancer therapy. Its efficacy can be further enhanced by combination with elacridar.
authors: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Ren-Yuan
authors: RY
authors: Bai
authors: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Verena
authors: V
authors: Staedtke
authors: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Teresia
authors: T
authors: Wanjiku
authors: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Michelle A
authors: MA
authors: Rudek
authors: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Avadhut
authors: A
authors: Joshi
authors: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Gary L
authors: GL
authors: Gallia
authors: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Gregory J
authors: GJ
authors: Riggins
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D006801:Humans; D008463:Mebendazole / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008527:Medulloblastoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects
chemical_list: D008463:Mebendazole