The influence of the structure of substituted benzodiazepines on their pharmacokinetic properties including the bioavailability, elimination half-life, clearance, and distribution volume in the human organism has been studied. The analysis was performed using the QSAR/QSPR method based on the Simplex representation of molecular structure. Completely adequate models capable of describing quantitatively the structure-pharmacokinetic properties relationship were obtained using the statistical methods of projection onto latent structures and multiple linear regression.Structural factors determining changes in the pharmacokinetic properties of substituted benzodiazepines are established on the basis of the obtained models.
Pharmacokinetics of amixin was studied after repeated administration (5 days) to animals. Perorally administered amixin is characterized by high bioavailability and is present in the circulation in high concentrations for a long time. The main pharmacokinetic parameters were estimated by the method of linear regression because of slow elimination of amixin from organs and tissues. Our results indicate that repeated treatment with amixin holds much promise for the prevention and therapy of chronic diseases (particularly hepatitides).
The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four biopharmaceutical classes according to their water solubility and membrane permeability characteristics and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following oral administration. When combined with the in vitro dissolution characteristics of the drug product, the BCS takes into account three major factors: solubility, intestinal permeability, and dissolution rate, all of which govern the rate and extent of oral drug absorption from immediate-release (IR) solid oral-dosage forms. The concept of BCS provides a better understanding of the relationship between drug release from the product and the absorption process. This report reviews the current status of computational tools in predicting the base properties (aqueous solubility, and passive absorption) of the BCS and explores the application of the Simplex representation of molecular structure (SiRMS) QSAR approach in absorption (bioavailability) research. The main advantages of SiRMS are consideration of the different physico-chemical properties of atoms, high robustness, predictivity, and interpretability of developed models that creates good opportunities for molecular design. The reliability of developed QSAR models as predictive virtual screening tools and their utility for targeted drug design were validated by subsequent synthetic and biological experiments. The SiRMS approach was implemented as "HiT QSAR" software. In addition, we provide our perspective on the progress of research into an in silico equivalent to the BCS.
Development of pathogenetic therapy of acute ethanol poisoning is of undoubted interest since such intoxication is often accompanied by a severe course and high lethality. Taking into account the peculiarities of the ethanol pathological action the treatment of such patients involves the use of drugs with the complex neuro-and hepatoprotective effects. Thereby, the studies for searching new pharmaceutical agents with a wide range of the pharmacological activity and economic availability continue. For a long time the object of researchers' attention is the chemical compound-pyridoxine-L-2-pyrrolidone-5-carboxylate (metadoxine). Till this moment a large number of the experimental data showing a diverse pharmacological profile of the drug action (antioxidant, antisteatotic, anti-inflammatory, antifibrotic, neurotropic) has been accumulated. Paying attention to the facts mentioned above our attention was focused on the detoxification action of metadoxine. Therefore, the aim of this work was to study the effect of metadoxine on the rate of excretion of ethanol and its metabolites in white rats in a preventive single introduction of the drug. The parameters of excretion of acetaldehyde, acetate and the unchanged ethanol with urine and feces have been chosen as a criterion for assessing the effectiveness of the process. Excretion of ethanol by lungs and sweat glands has not been studied because of a negligible contribution of these pathways in the process of ethanol elimination. It has been determined that intraperitoneal introduction of metadoхine in the dose of 200 mg/kg 30 min prior ethanol introduction (orally in the dose of 1 g/kg) accelerates the rate of elimination of ethanol and its metabolites (acetaldehyde and acetate) in rats.
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