LC and LC–MS/MS studies for the identification and characterization of degradation products of acebutolol / 药物分析学报

The aim of the present investigation was to demonstrate an approach involving use of liquid chromatography (LC) and liquid chromatography-mass spectrometry (LC–MS) to separate, identify and characterize very small quantities of degradation products (DPs) of acebutolol without their isolation from the reaction mixtures. The drug was subjected to oxidative, hydrolytic, thermal and photolytic stress conditions as per International Conference on Harmonization (ICH) guideline Q1A(R2). Among all the stress conditions the drug was found to be labile in hydrolytic (acidic & basic) and photolytic stress conditions, while it was stable in water-induced hydrolysis, oxidative and thermal stress conditions. A total of four degradation products were formed. A C18 column was employed for the separation of all the DPs on a gradient mode by using high-performance liquid chromatography (HPLC). All the DPs were characterized with the help of their fragmentation pattern and the masses obtained upon LC–MS/MS and MSn analysis. All the hitherto unknown degradation products were identified as 1-(2-(2-hydroxy-3- (isopropylamino)propoxy)-5-(amino)phenyl)ethanone (DP-I), N-(4-(2-hydroxy-3-(isopropylamino) propoxy)-3-acetylphenyl)acrylamide (DP-II), 1-(2-(2-hydroxy-3-(isopropylamino)propoxy)-5-(hydroxymethylamino) phenyl)ethanone (DP-III) and 1-(6-(2-hydroxy-3-(isopropylamino)propoxy)-2,3-dihydro- 2-propylbenzo[d]oxazol-5-yl)ethanone (DP-IV). Finally the in-silico carcinogenicity and hepatotoxicity predictions of the drug and all the DPs were performed by using toxicity prediction softwares viz., TOPKAT, LAZAR and Discovery Studio ADMET. The results of in-silico toxicity studies revealed that acebutolol (0.967) and DP-I (0.986) were found to be carcinogenic, while acebutolol (0.490) and DP-IV (0.437) were found to be hepatotoxic.

Acebutolol, a Cardioselective Beta Blocker, Promotes Glucose Uptake in Diabetic Model Cells by Inhibiting JNK-JIP1 Interaction

The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation, becomes a potential target for drug development of type 2 diabetes. To discover the inhibitors of JNK-JIP1 interaction, we screened out 30 candidates from 4320 compound library with In Cell Interaction Trap method. The candidates were further confirmed and narrowed down to five compounds using the FRET method in a model cell. Among those five compounds, Acebutolol showed notable inhibition of JNK phosphorylation and elevation of glucose uptake in diabetic models of adipocyte and liver cell. Structural computation showed that the binding affinity of Acebutolol on the JNK-JIP1 interaction site was comparable to the known inhibitor, BI-78D3. Our results suggest that Acebutolol, an FDA-approved beta blocker for hypertension therapy, could have a new repurposed effect on type 2 diabetes elevating glucose uptake process by inhibiting JNK-JIP1 interaction.

Interpenetrating polymer network of cross-linked blend microspheres for controlled release of Acebutolol HCl.

Carbohydrate polymeric blend microspheres consisting of chitosan (CS) and poly (vinyl alcohol) (PVA) were prepared by water-in-oil (W/O) emulsion method. These microspheres were crosslinked with glutaraldehyde and loaded with Acebutolol HCl, an anti hypertensive drug. The microspheres were characterized by Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), X-Ray diffraction (X-RD) and Scanning electron microscopy (SEM).The FTIR spectroscopy explains the crosslinking between the CS-PVA. DSC& X-RD indicated the molecular level distribution of Acebutolol HCl drug in the polymer matrix. The SEM of the microspheres suggested the formation of spherical particles. Swelling experiments on the microspheres provided important information on drug diffusion properties. Release data have been analyzed using an empirical equation to understand the nature of transport of drug containing solution through the polymeric matrices. The controlled release characteristic of the matrices for Acebutolol HCl was investigated in pH 7.4 media. The results indicate that the drug was released in a controlled manner up to 10 h.