Interaction of PEGylated anti-hypertensive drugs, amlodipine, atenolol and lisinopril with lipid bilayer membrane: A molecular dynamics simulation study.

The interaction of PEGylated anti-hypertensive drugs, amlodipine, atenolol and lisinopril with lipid bilayer membrane dimyristoylphosphatidylcholine (DMPC) has been studied in nine different simulation systems consisting of 128 lipid molecules and appropriate number of water molecules by molecular dynamics method and by utilizing GROMACS software. The influences of PEGylation on the mentioned drugs and the differences in application of two types of spacer molecules on the performance of drugs and DMPC membrane have been evaluated and mass density of the components in the simulation box, mean square displacement (MSD), electrostatic potential, hydrogen bonding, radial distribution function (RDF), area per lipid, order parameter, and angle distribution of the component molecules including drug, DMPC and PEG has been investigated. Furthermore, umbrella sampling analysis indicated that, PEGylation of the drugs made amlodipine to behave more hydrophilic, whereas in case of lisinopril and atenolol, PEGylation made these drugs to behave more hydrophobic. In almost all of the simulated systems, PEGylation increased the diffusion coefficient of the drugs.

Transdermal delivery of atenolol: effect of prodrugs and iontophoresis.

Inadequate skin permeability is the main challenge encountered in the transdermal drug delivery and to solve this crisis physical and chemical enhancement techniques are being developed. The aim of the present investigation was to study the combined effect of two such techniques, iontophoresis and esterification, on the transdermal delivery of atenolol. A series of ester prodrugs of atenolol were synthesized, characterized and studied for physicochemical properties and stability. In vitro permeation studies were carried out for atenolol and prodrugs at different donor concentrations (5, 10, and 20 mM) by passive process and iontophoresis (0.5 mA/cm(2)). Evaluation of the physicochemical parameters showed significant increase in lipophilicity and slight reduction in pK value in the ester prodrugs compared to parent drug. Stability studies revealed higher stability at pH 4 than pH 6. Prodrugs significantly enhanced the transdermal flux of atenolol in passive process while in iontophoresis the enhancement ranged from 1.4 to 2.7 fold compared to atenolol. In the prodrug series, permeation rate increased with increase in the length of alkyl side chain up to the addition of 5 carbon units, but thereafter no specific pattern was recorded in both passive and iontophoretic process. The steady state flux was highest in atenolol valerate (1.48 micromol/cm(2) h), which shows the promise of meeting the desired permeation rate (3.0- 31.0 micromol/ h) for maintenance of the therapeutic level in a 70 kg human.

Unusual products of the aqueous chlorination of atenolol.

The reaction of the drug atenolol with hypochlorite under conditions that simulate wastewater disinfection was investigated. The pharmaceutical reacted in 1h yielding three products that were separated by chromatographic techniques and characterized by spectroscopic features. Two unusual products 2-(4-(3-(chloro(2-chloropropan-2-yl)amino)-2-hydroxypropoxy)phenyl) acetamide and 2-(4-(3-formamido-2-hydroxypropoxy)phenyl) acetamide were obtained along with 2-(4-hydroxyphenyl) acetamide. When the reaction was stopped at shorter times only 2-(4-(3-amino-2-hydroxypropoxy)phenyl) acetamide and the dichlorinated product were detected. Tests performed on the seeds of Lactuca sativa show that chlorinated products have phytotoxic activity.

Identification and structural characterization of biodegradation products of atenolol and glibenclamide by liquid chromatography coupled to hybrid quadrupole time-of-flight and quadrupole ion trap mass spectrometry.

In this paper we report about the biodegradation of the beta-blocker atenolol and the hypoglycaemic agent glibenclamide. The biodegradation tests were performed in batch reactors under aerobic conditions, using as inocculums sewage sludge from a conventional activated sludge treatment and a laboratory-scale membrane bioreactor. Pharmaceuticals were used as sole carbon sources, spiked at 50ng/L and 10mg/L concentrations. Quadrupole time-of-flight mass spectrometry coupled to ultra-high-pressure liquid chromatograph was used for the screening and the structural elucidation of biodegradation products. A microbial metabolite of atenolol with [M+H](+) at 268 was detected in the positive electrospray ionization mode. This new compound was determined to be a product of microbial hydrolysis of the amide of the parent compound. Biodegradation of glibenclamide by activated sludge proceeded via bacterial hydroxylation of the cyclohexyl ring, which resulted in formation of metabolite with a protonated molecule, [M+H](+)=510. MS(3) experiments performed by hybrid quadrupole linear ion trap (QqLIT) mass spectrometry coupled to high-performance liquid chromatography enabled further structural elucidation of the identified metabolites. Moreover, the highly sensitive QqLIT instrument in the MRM mode enabled the detection of parent compounds and one of the microbial metabolites identified in real wastewater samples. The methodology used in this study permitted for the first time the identification and detection of biodegradation product of beta-blocker atenolol in real wastewater samples.

Synthesis and binding to beta-adrenergic receptors of p-aminobenzyl analogues of practolol and atenolol.

The p-aminobenzyl analogues (8a and 8b, respectively) of the cardioselective beta-adrenergic receptor antagonists practolol and atenolol were prepared from the corresponding phenoxymethyloxiranes in 30 and 13% yields, respectively. The dissociation constants for the beta-adrenergic receptor were measured in membrane preparations of rat heart and lung. In membranes from the heart (which contain mostly beta 1-adrenergic receptors), the affinities of the derivatives and parent compounds were similar. By contrast, in membranes from the lung (which contain mostly beta 2-adrenergic receptors), the derivatives were more potent than the parent compounds. Thus, the cardioselectivities of the p-aminobenzyl analogues 8a and 8b were about one-sixth those of the respective parents.