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In this study, the interaction of valsartan (VAL), an angiotensin II receptor antagonist, with cationic surfactant cetyltrimethylammonium bromide (CTAB) was investigated. The effect of cationic micelles on spectroscopic and acid-base properties of VAL was carried out using UV spectrophotometry at physiological conditions (pH 7.4). The binding of VAL to CTAB micelles implied a shift in drug acidity constant (pK(a)(water) - pK(a)(micelle) = 1.69) proving the great affinity of VAL dianion for the positively charged CTAB micelle surface. To quantify the degree of VAL/CTAB interaction, two constants were calculated by using mathematical models: micelle/water partition coefficient (K-x) and drug/micelle binding constant (K-b). The decrease of K-x with VAL concentration, obtained by using pseudo-phase model, is consistent with an adsorption-like phenomenon. From the dependence of differential absorbance at lambda = 295 nm on CTAB concentration, by using mathematical model that treats the solubilization of VAL dianion as its binding to specific sites in the micelles (Langmuir adsorption isotherm), the binding constant (K-b = (2.50 +/- 10.49) x 10(4) M-1) was obtained. Binding constant VAL/CTAB was also calculated using micellar liquid chromatography (MLC).

In this study, the interaction of hydrochlorothiazide (HCT), benzothiadiazine diuretic, with cationic surfactant cetyltrimethylammonium bromide (CTAB) was investigated. The effect of cationic micelles on the spectroscopic and acid-base properties of HCT was studied at pH 10.5. The binding of HCT to CTAB micelles implied a shift in drug acidity constant (pK(a)(water) - pK(a)(micelle) =0.46) proving the greater affinity of HCT dianion for the positively charged CTAB micelle surface. From the dependence of differential absorbance at lambda = 355 nm on CTAB concentration, by using mathematical model that treats the solubilization of HCT dianion as its binding to specific sites in the micelles (Langmuir adsorption isotherm), the binding constant K-b = (1.17 +/- 0.16) x 10(4) mol(-1) dm(3) was obtained. By using pseudo-phase model, the partition coefficient between the bulk water and CTAB micelles, K-x, was calculated from both differential absorbance Delta A(355), K-x =(6.18 +/- 0.64) x 10(4) mol((1) dm(3), and first-order derivative amplitude D-1(250.1), K-x =(5.47 +/- 0.56) x 10(4) mol((1) dm(3).

In this paper, twenty-two 17 beta-carboxamide steroids were synthesized from five corticosteroids (hydrocortisone, prednisolone, methylprednisolone, dexamethasone and betamethasone) in two steps. The first step was periodic acid oxydation of these corticosteroids to corresponding cortienic acids and the second step was amidation of thus obtained cortienic acids with esterified L-amino acids. These compounds are potential soft corticosteroids with local anti-inflammatory activity in the skin. Parallel artificial membrane permeability assay (PAMPA) was applied in order to predict permeability and retention of these compounds in human skin. Comparison of permeability and retention parameters between 17 beta-carboxamide steroids and corresponding corticosteroids was performed. Compounds with significantly higher retention were identified and the derivative that does not have significantly higher permeability was underlined. Molecular structures of all compounds were optimized by use of Gaussian semiempirical/PM3 method. Geometrical, thermodynamic, physicochemical and electronical molecular parameters of the optimized structures were calculated and quantitative structure-property relationship (QSPR) analysis was performed in order to explain permeability and retention of these compounds. ANN-, PLS- and MLR-QSPR models were created. Quality of these models was evaluated by commonly used statistical parameters and the most reliable models were selected. Analyzing descriptors in the selected models, main molecular properties that influence permeability and retention in the PAMPA artificial membrane were identified. Based on these data, further structural modifications could be applied in order to increase retention without significant increase of permeability, which can positively affect potential local antiinflammatory activity of these compounds. Selected QSPR models could be used as in silico tool for predicting human skin permeability and retention of novel 17 beta-carb

In this paper, human skin and corneal permeability of twenty-two newly synthesized 17 beta-carboxamide steroids was predicted using biopartitioning micellar chromatography (BMC). These compounds are potential soft glucocorticoids with local anti-inflammatory activity when applied to the skin or eye. BMC systems are used to simulate physicochemical properties of human skin (BMC-skin) and cornea (BMC-cornea). Micellar mobile phase, consisted of 0.04 M solution of polyoxyethylene (23) lauryl ether (Brij 35), was prepared at different pH values - 5.50 (BMC-skin) and 7.50 (BMC-cornea). Retention factors (k), obtained by use of BMC, were calculated for all newly synthesized 17 beta-carboxamide steroids as well as for parent glucocorticoids (hydrocortisone, prednisolone, methylprednisolone, dexamethasone and betamethasone). Good correlation was obtained between BMC-skin retention factors and permeability coefficients calculated by use of the artificial membrane that simulates stratum corneum of the human skin. Quantitative structure-retention relationship (QSRR) study was performed in order to explain retention factors of these compounds in the tested BMC systems. ANN-QSRR(k), PLS-QSRR(k) and MLR-QSRR(k) models, created by use of BMC-skin retention data, were compared and optimal model (PLS-QSRR(k)) was selected. Molecular descriptors of the selected model indicate that lipophilicity and number of short C C fragments of tested compounds have the strongest influence on the retention in the BMC-skin system and presumably on their in vivo permeability through human skin. The same model can be applied to the BMC-cornea system and the same conclusion can be drawn for corneal permeability. This model could be used as a predictive tool for the synthesis of novel 17 beta-carboxamide steroids with desirable permeability through human skin or cornea, depending on their potential pharmacological application.