title: Murine toxicology and pharmacokinetics evaluation of retinoic acid metabolism blocking agent (RAMBA), VN/12-1.
abstract: OBJECTIVE
  Novel retinoic acid metabolism blocking agent (RAMBA), VN/12-1, is a highly potent anti-cancer agent that induces autophagy. Its combination with autophagy inhibitor chloroquine (CHL) has been shown to synergistically enhance apoptosis in breast cancer cells. The purpose of this study was to determine the toxicity and pharmacokinetic profile of VN/12-1 and its combination with CHL.
  
  
  METHODS
  Preliminary toxicology of VN/12-1 was determined using female SCID mice (n = 4 for each group). ATRA was used for comparison. We selected four different doses of VN/12-1 and ATRA. Two of the doses were low and less frequent (2.5 and 5 mg/kg twice a week), and the remaining doses were high and more frequent (10 and 20 mg/kg every day). The dose of CHL was 50 mg/kg twice a week. For pharmacokinetic (PK) study, 20 mg/kg of VN/12-1 was injected subcutaneously (s.c.) into the mice, and their plasma was collected at various intervals (n = 2) and analyzed by HPLC.
  
  
  RESULTS
  The lower and less frequent doses of VN/12-1 and ATRA were found to be least toxic. However, high and more frequent doses of these compounds were toxic to the mice. PK results showed that VN/12-1 has a half-life of 6 h. The area under the curve (AUC) for VN/12-1 was 83.78 h μg/ml.
  
  
  CONCLUSIONS
  VN/12-1 and ATRA are non-toxic when used as 5 mg/kg twice a week as single agents or in combination with CHL. The favorable PK properties of VN/12-1 can potentially be used for its further advanced pre-clinical and clinical development.
authors.affiliation: Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA. agodbole@som.umaryland.edu
authors.forename: Abhijit M
authors.initials: AM
authors.lastname: Godbole
authors.forename: Puranik
authors.initials: P
authors.lastname: Purushottamachar
authors.forename: Marlena S
authors.initials: MS
authors.lastname: Martin
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D001343:Autophagy / Q000187:drug effects; D002738:Chloroquine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D007279:Injections, Subcutaneous; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D018675:Toxicity Tests; D014212:Tretinoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: C575619:4-(1H-imidazol-1-yl)retinoic acid methyl ester; D000970:Antineoplastic Agents; D007093:Imidazoles; D014212:Tretinoin; D002738:Chloroquine