Relationships between the antidotal efficacy and structure, PK/PD parameters and bio-relevant molecular descriptors of AChE reactivating oximes: inclusion and integration to biopharmaceutical classification systems.
BACKGROUND
The therapeutic outcome of oximes used as reactivators of phosphorylated human acetylcholinesterase (AChE) is influenced, among other factors, by their biological distribution, their in vivo ability to achieve the nucleophilic attack and their affinity for the anionic center of the intact/inhibited AChE.


METHODS
An in silico evaluation of the molecular descriptors and biopharmaceutical properties of 454 set of oximes has been achieved. The available pharmacokinetic (PK) data was analyzed, in an attempt to illustrate their common characteristics and particularities. Based on the observed high water solubility and low permeability across biological barriers, we applied the officially adopted classification systems based on biopharmaceutical properties to identify the existing biopharmaceutical differences between the various oxime entities and to predict their in vivo fate.


CONCLUSIONS
The structural differences of the organophosphorus compounds (OP) and the available oximes reactivators of OP-inhibited AChE generate distinct toxicokinetic or PK profiles. The tissue compartment specific distribution is one of the key elements for assessment of reactivating efficiency. The distribution through highly specialized barriers, such as blood-brain barrier remains a considerable challenge. The high solubility - low permeability biopharmaceutical profile of oximes can be used to suggest the possible involvement of active transport systems.
Romanian Academy, Medical Sciences Section , Calea Victoriei no. 125, Bucharest - 010071 , Romania.
Victor
V
Voicu
Flavian Ştefan
FŞ
Rădulescu
Andrei
A
Medvedovici
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D000931:Antidotes / Q000737:chemistry / Q000493:pharmacokinetics*; D001702:Biopharmaceutics / Q000145:classification* / Q000379:methods; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D010091:Oximes / Q000737:chemistry / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
D000931:Antidotes; D002801:Cholinesterase Reactivators; D010091:Oximes; D000110:Acetylcholinesterase
AChE reactivators; biodistribution; biopharmaceutical classifications; organophosphorus intoxication; oximes; pharmacokinetics