title: The forgotten or underestimated relevance of biopharmaceutical-based assessments for the oral absorption studies of oxime reactivators.
abstract: BACKGROUND
  The absorption, distribution, metabolism, excretion and toxicity (ADME(T)) of oxime reactivators have been assessed with respect to their polarity, a fundamental requirement for their specific mechanism of action in the intoxication with organophosphorous compounds. The limitations of the therapeutic outcome have been associated not only with the severity of intoxication and to particularities of the toxicants, but also to the reduced lipophilicity and consequent restricted permeability across biological barriers.
  
  
  METHODS
  This article inventories the plethora of mnemotic rules developed throughout the years for defining chemical spaces where drugs share one or more structural and ADME(T) characteristics. Their applicability to oxime is analyzed, especially in relation to intestinal absorption and brain distribution. Other aspects of oximes for antidotal outcome are also reviewed.
  
  
  CONCLUSIONS
  The drugability rules are not applicable to oxime reactivators, because the increase in lipophicity and consequent improved permeability across biological barrier comes together with amplified (neuro)toxicity and reduced reactivating capacity. The available data suggest a high solubility and reduced metabolism, assigning the quaternary oximes to the fourth class of Biopharmaceutical Classification Systems. Reliance upon oral absorption data for designing safe centrally acting oximes can be of potential value, with adequate characterization of uptake-influx transporters interplay.
authors.affiliation: a Department of Pharmacology, Toxicology and Clinical Psychopharmacology , University of Medicine and Pharmacy 'Carol Davilla' , Bucharest , Romania.|b Medical Science Section , Romanian Academy , Bucharest , Romania.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Voicu
authors.affiliation: c Department of Analytical Chemistry , University of Bucharest , Bucharest , Romania.
authors.forename: Andrei Valentin
authors.initials: AV
authors.lastname: Medvedovici
authors.affiliation: d Department of Forensic Dentistry, Graduate School of Medical and Dental Sciences , Tokyo Medical and Dental University , Tokyo , Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sakurada
authors.affiliation: e Department of Forensic Chemistry, Toxicology Section , National Research Institute of Police Science, National Police Agency , Kashiwa City , Chiba , Japan.
authors.forename: Hikoto
authors.initials: H
authors.lastname: Ohta
authors.affiliation: f Faculty of Pharmacy , University of Medicine and Pharmacy Carol Davila , Bucharest , Romania.
authors.forename: Flavian Ștefan
authors.initials: FȘ
authors.lastname: Rădulescu
authors.affiliation: f Faculty of Pharmacy , University of Medicine and Pharmacy Carol Davila , Bucharest , Romania.
authors.forename: Dalia Simona
authors.initials: DS
authors.lastname: Miron
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D002801:Cholinesterase Reactivators / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D015195:Drug Design; D006801:Humans; D062025:Organophosphate Poisoning / Q000188:drug therapy*; D010091:Oximes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010539:Permeability; D012995:Solubility; D014018:Tissue Distribution
chemical_list: D000931:Antidotes; D002801:Cholinesterase Reactivators; D010091:Oximes
keywords: Acetylcholinesterase reactivators; Biopharmaceutics Classification Systems; brain disposition; oral absorption; oximes