Hydrophobicity/hydrophilicity descriptors obtained from extrapolated chromatographic retention data as modeling tools for biological distribution: Application to some oxime-type acetylcholinesterase reactivators
University of Medicine and Pharmacy Carol Davilla, Department of Pharmacology, Toxicology and Clinical Psychopharmacology, #8 Floreasca Street, Bucharest 014461, RomaniaJournal of pharmaceutical and biomedical analysis (Impact Factor: 2.98). 02/2010; 52(4):508-16. DOI: 10.1016/j.jpba.2010.02.004
Chromatographic retention data obtained from interactions between some oxime-type compounds and different stationary phases (involving hydrophobic interaction, ion pairing formation availability, pi-pi, H-bonding, dipole-dipole, ion-dipole, electrostatic interaction and glycoprotein binding ability) have been studied. The logarithms of the capacity factors extrapolated at 0% or 100% organic solvent, resulting from the functional dependencies between retention and mobile phase composition, were used for estimation of different kind of hydrophobicity or hydrophilicity descriptors (HHDs) of these compounds. The conditions of the chromatographic separation were chosen as close as possible to in-vivo conditions (the aqueous component of the mobile phase has a pH in the physiologic interval 6.8-7.2, 0.9% sodium chloride was added to reproduce ionic strength and isotonic character, and the temperature was set at 37 degrees C). These descriptors characterizing the partition between stationary/mobile phases through specific interactions may be directly used for correlation to biological distribution processes, such as penetration of the blood/brain barrier. Oxime-type compounds used as acetylcholinesterase (AChE, E.C.220.127.116.11) reactivators have been considered for the retention study. The choice is supported by their use in the therapy of acute intoxication with organophosphorus AChE inhibitors (OPIs, especially nerve agents and pesticides), a rather complicated chemistry in solution and a relative lack of data about computational molecular descriptors used for modeling biological partition/distribution. Some correlations between the determined descriptors and computational values have also been discussed.
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ABSTRACT: This review covers a novel approach to comparing methods, based on the sum of ranking differences (SRD). Many method-comparison studies suffer from ambiguity or from comparisons not being quite fair. This problem can be avoided if there are differences between ideal and actual rankings. The absolute values of differences for the ideal and actual ranking are summed up and the procedure is repeated for each (actual) method. The SRD values obtained such a way order the methods simply. If the ideal ranking is not known, it can be replaced by the average (maximum or minimum of all methods or by a known sequence).SRD corresponds to the principle of parsimony and provides an easy tool to evaluate the methods: the smaller the sum the better the method. Models and other items can be similarly ranked.Validation can be carried out using simulated random numbers for comparison: an empirical histogram (bootstrap-like) shows whether the SRD values are far from random.Two case studies (clustering of HPLC columns and prediction of retention data) illustrate and validate the applicability of this novel approach to comparing methods.The technique is entirely general; it can be used in different fields (e.g., for stationary-phase (column) selection in chromatography, model and descriptor selection, comparing analytical and chemometric techniques, determination of panel consistency, etc.). The only prerequisite is that the data can be arranged in matrix form without empty cells.TrAC Trends in Analytical Chemistry 01/2010; 29(1):101-109. DOI:10.1016/j.trac.2009.09.009 · 6.47 Impact Factor
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ABSTRACT: Undoubtedly, the use of oximes represents real progress in counteracting intoxications with organophosphates (OP), through potentiating antidotal effects of atropine. The penetration extent of these compounds through the blood-brain barrier (BBB) to significantly reactivate phosphorylated or phosphonylated acetylcholinesterase (AChE) in the brain still remains a debatable issue. Penetration of biological barriers by oximes was investigated mainly through determination of several quantitative parameters characterizing digestive absorption and BBB penetration. A weak penetration of biological barriers could be concluded from the available experimental data. The functional parameters/therapeutic effects following the penetration of oximes through BBB, more precisely the antagonism of OP-induced seizures and hypothermia, prevention of brain damage and respiratory center protection, leading to the final end-point, the survival of intoxicated organisms, are of high interest. It seems obvious that oximes are weakly penetrating the BBB, with minimal brain AChE reactivation (<5%) in important functional areas, such as the ponto-medullar. The cerebral protection achieved through administration of oximes is only partial, without major impact on the antagonism of OP-induced seizures, hypothermia and respiratory center inhibition. The antidotal effects probably result from synergic effects of other PD properties, different from the brain AChE reactivation process. Oxime structures especially designed for enhanced BBB penetration, through potentiating the hydrophobic characteristics, more often produce neurotoxic effects. Certainly, obtaining oximes with broad action spectrum (active against all OP types) would make a sense, but certainly, such a target is not achievable only through the increase in their penetrability in the brain.Journal of Applied Toxicology 11/2010; 30(8):719-29. DOI:10.1002/jat.1561 · 2.98 Impact Factor
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ABSTRACT: In the present work, the chromatographic behavior of eight selenium species, namely selenites (Se(IV)), selenates (Se(VI)), seleno-DL-methionine (Se-Met), selenocystine (Se-Cyst), selenocystamine (Se-CM), selenourea (Se-U), dimethylselenide ((CH(3))(2) Se) and dimethyldiselenide ((CH(3))(2) Se(2)), was investigated under different stationary and mobile phase conditions, in an effort to unravel secondary interferences in their underlying elution mechanism. For this purpose, two end-capped and a polar-embedded reversed-phase stationary phases were employed using different mobile phase conditions. Retention factors (log k(w)) were compared with octanol-water distribution coefficients (log D) as well as with log k(w) values on two immobilized artificial membrane (IAM) columns and two immobilized artificial plasma proteins stationary phases, obtained in our previous work. The role of electrostatic interactions was confirmed by introducing the net charge of the investigated Se species as an additional term in the log k(w)/log D interrelation, which in most cases proved to be statistically significant. Principal component analysis of retention factors on all stationary phases and octanol-water log D values, however, showed that the elution of the investigated selenium species is mainly governed by partitioning mechanism under all different chromatographic conditions, while the pH of the mobile phase and the special column characteristics have only a minor effect.Journal of Separation Science 02/2011; 34(4):376-84. DOI:10.1002/jssc.201000771 · 2.74 Impact Factor
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