Relationship between physicochemical characteristics and pharmacokinetic parameters of 1,4-benzodiazepine derivatives

Abstract

A rational targeted search for new effective drugs of the benzodiazepine group should be based on established relationships between the physicochemical properties of compounds and their pharmacological activity, the direction and rate of biotransformation, and the pharmacokinetic parameters [1]. Correlations between these factors make possible drawing reliable judgments about the rate of absorption from the gastrointestinal tract, the time of attaining maximum concentration in the blood, the time of circulation in the organism, and the rates of accumulation and elimination of new drugs, based on the results of analysis of the known data for analogous substances.This aim of this study was to determine some important physicochemical characteristics (dissolution rate constant, diffusion rate constant, lipophilicity constant) of a series of 1,4-benzodiazepine derivatives and to establish relationships between these values and the parameters of pharmacokinetics of these compounds in rats. EXPERIMENTAL CHEMICAL PARTThe study was performed on a series of 1,4-benzodiazepine derivatives with structures differing from each other in the nature of the chemical radicals at the N 1 , C 3 , and C 7 positions of the benzodiazepine cycle and the C 2 position of the phenyl ring (Table 1).(a) Determining the dissolution rate constants (K sol ) of drugs. The measurements were performed for fractions of the parent substances with a particle size not exceeding 0.2 mm, which were separated by sieving powdered compounds through a standard silk sieve No. 31. A sol-free filter with a weighed amount of the powdered drug was placed in a dry basket. The basket was immersed into a dissolution medium, the rotary drive was switched on, and the dissolution kinetics was measured by determining the concentration of the dissolved compound at certain time intervals. The rate of basket rotation was 100 rpm, and the solution samples (2.5 ml) were taken every 10 min over a 60-min period (with replenishing the volume of the dissolution medium by adding the same amount of pure solvent). The drug concentration in the samples was determined by UV spectrophotometry. The drug dissolution process was described in terms of the first-order kinetic equation, and the K sol values were determined by least squares [2].(b) Determining the diffusion rate constants (K d ) of drugs. The diffusion constants were determined using a membrane model simulator of the Sartorius 16750SM type (Germany). The membrane separating the donor and acceptor chambers was made of poly(vinyl acetate) and impregnated with lipids (fatty alcohols and fatty acids). Depending on the combination of impregnating lipid components, it was possible to simulate membranes of the stomach and intestinal walls [2].(c) Determining the lipophilicity constants (log K w ) of drugs. The characteristics of lipophilicity were determined by reverse-phase HPLC on a 4.6´250 mm column with 583 0091-150X/04/3811-0583

Bacteriostatic and Bactericidal effects of ethyl acetate root bark extract of Terminalia avicennioides on Methicillin-resistant Staphylococcus aureus

“…A similar finding was reported on the anti-MRSA of T. avicennioides; though, the leave part of the plant was used, but was found to be potent against MRSA isolated from Primary School Pupils in Ekiti State, Nigeria (Ajibade and Akinruli, 2016).This is an indication that harnessing T. avicennioides is advancement of the search for novel and viable anti-MRSA agent.The possible mechanism of action of the bioactive fraction of the extract against the test organism, MRSA, may be deduced from the presence of the functional groups. Previous studies (Hollosy et al, 2002;Litvin et al, 2004) indicated that halogen substituents on aryl rings resulted in compound with improved biological activity, hence, incorporation of halogen atoms into drug candidates have generally been correlated with increased lipophilicity; this enhances the penetration of agents into cells through the lipid membrane. The alkyl halides in the bioactive fractions may have explained the bactericidal mechanism of action of the agent against the MRSA.…”

Experimental versus theoretical log D7.4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

“…The majority of the well‐known benzodiazepines, herein referred to as classic benzodiazepines, have comparatively high values for lipophilicity and can therefore partition with ease across cellular membranes and accumulate in areas of the body that are high in lipids . Furthermore, benzodiazepines also have high volumes of distribution (V d ) such as diazepam with a V d at steady state of 0.88–1.39 L kg −1 . The lipophilicity (as log P) of some NPS‐benzodiazepines has already been published in literature …”

“…18,19 Furthermore, benzodiazepines also have high volumes of distribution (V d ) such as diazepam with a V d at steady state of 0.88-1.39 L kg −1 . [20][21][22][23] The lipophilicity (as log P) of some NPS-benzodiazepines has already been published in literature. 24 The acid-base dissociation constant (pK a ) of a compound is typically investigated during pharmaceutical development and plays an important role when used in conjunction with other parameters, such as molecular weight and lipophilicity.…”