Title : The forgotten or underestimated relevance of biopharmaceutical-based assessments for the oral absorption studies of oxime reactivators - Voicu_2016_Expert.Opin.Drug.Metab.Toxicol__1 |
Author(s) : Voicu VA , Medvedovici AV , Sakurada K , Ohta H , Radulescu FS , Miron DS |
Ref : Expert Opin Drug Metab Toxicol , :1 , 2016 |
Abstract :
INTRODUCTION: 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. Areas covered: 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. Expert opinion: 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. |
PubMedSearch : Voicu_2016_Expert.Opin.Drug.Metab.Toxicol__1 |
PubMedID: 27144662 |
Voicu VA, Medvedovici AV, Sakurada K, Ohta H, Radulescu FS, Miron DS (2016)
The forgotten or underestimated relevance of biopharmaceutical-based assessments for the oral absorption studies of oxime reactivators
Expert Opin Drug Metab Toxicol
:1
Voicu VA, Medvedovici AV, Sakurada K, Ohta H, Radulescu FS, Miron DS (2016)
Expert Opin Drug Metab Toxicol
:1