The forgotten or underestimated relevance of biopharmaceutical-based assessments for the oral absorption studies of oxime reactivators

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.

KEYWORDS:

• Acetylcholinesterase reactivators
• Biopharmaceutics Classification Systems
• brain disposition
• oral absorption
• oximes

Article highlights

• Oximes reactivators of acethylcholinesterase inhibited by organophosphorous compounds are polar entities with limited permeability across biological barriers.

• The mnemotic rules for screening of ADME(T) features are almost unanimously based on the overemphasized value of lipid water partition coefficients.

• Designing new oximes by incriminating only the restricted permeability increases to odds of failure, increasing the toxicity of resulting entities and reducing the efficiency of nucleophilic attack.

• The role uptake-influx transporter interplay is emphasized, based on solubility and metabolic stability of the antidotal oxime.

• New strategies of oxime design may be developed starting from the elucidation of the reduced, although existing permeability.

• Experimental data on oral absorption and underlying mechanisms can help in improving brain delivery of polar and effective reactivators.

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Declaration of interests

This work was supported by a grant of the Romanian Ministry of National Education, CNCS-UEFISCDI project number PN-II-ID-PCE-2012-4-0651. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.