Search

This paper presents basic data on organophosphonate (OP) mechanisms of action, especially by toxicokinetic/toxicodynamic (TK/TD) process correlations. It is generally accepted that at least during onset of OP biological systems interaction, blood and tissue cholinesterase's inhibition represents OP exposure marker and initiating mechanisms for toxicodynamic effects, characteristic for cholinergic crisis. OP penetrability of various biological barriers conditioning TK characteristics are determined by a series of physico-chemical properties. Non-cholinergic effects, direct interactions with cellular structures and subsequent effects (excitotoxicity) triggered by cholinergic crisis are also briefly presented. Opposed to these OP TK/TD characteristics, the authors analysed the pharmacokinetic/pharmacodynamic (PK/PD) characteristics and their correlations for oximes, as basic OP antidotes, besides atropine and anticonvulsants. Phosphorilated cholinesterasis reactivators are mono or bispyridinium derivatives with quaternary ammonium atoms, high water solubility, ionized at physiological pH, distribution in extra-cellular space, very low digestive absorption and blood-brain barrier (BBB) penetrability. OP nerve gas acute toxicity is correlated with anti-acetylcholinesterase (AChE) activity and partition coefficient. The toxicity rank seems to be determined by lipophilicity, besides their specific AChE inhibitory property. It has the effect that acute toxicity is the resultant of a TD process closely linked and dependent in vivo upon molecular descriptors determinant for the TK process. For cholinesterasis reactivators, molecular and PK characteristics limit their effects, especially to the peripheral level. The absent or much reduced BBB penetrability allowed some researchers to suggest that reactivators' penetration and presence at central level are not necessary. The study of PK/PD correlations, molecular descriptors and biological membrane permeability of oximes can better define their antidotal effects mechanisms and, maybe, open a new perspective for field development.

The World Health Organization (WHO) rules (1996) recommend in chapter 3 ‘‘Technical data for regulatory assessment’’ that information for marketing authorization should contain among others in-documentation, equivalence data (comparative bioavailability, pharmacodynamic or clinical studies), and comparative in vitro dissolution tests. European rules concerning evaluation of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98) specify in chapter 5.2: ‘‘Dissolution studies are always necessary and consequently required. In vitro dissolution testing forms a part of the assessment of a bioequivalence waiver’’. The consequence is that over the last years all over Europe dissolution studies were connected to bioequivalence studies and the natural tendency was to correlate the results obtained in the pair studies in order to obtain models allowing dissolution results as predictor for in vivo results. Let us consider only as a mnemotechnique, the living body as a ‘‘mathematical operator’’ which transforms parameters characterizing dissolution curves in pharmacokinetic parameters associated to plasma levels curves.