Identification and characterization of the in-vivo metabolites of the novel soluble epoxide hydrolase inhibitor EC5026 using liquid chromatography quadrupole time of flight mass spectrometry.

EC5026 is a novel soluble epoxide hydrolase inhibitor being developed clinically to treat neuropathic pain and inflammation. In the current study, we employed the LC-ESI-Q-TOF-MS/MS technique to identify four in-vivo phase-I metabolites of EC5026 in rat model, out of which three were found to be novel. The identified metabolites include aliphatic hydroxylation, di-hydroxylation, terminal desaturation, and carboxylation. No phase-II metabolites were found. The pharmacokinetic profile of identified metabolites was established after a single oral dose of EC5026 to Wistar rats. The Tmax of the drug and metabolites were found to be in the range of 1-2 hours and 4-12 hours, respectively. The major metabolites M1 and M2 were found to have more than 2-fold (263.87% AUC) and equivalent exposure (96.33% AUC) compared to the parent drug, respectively. Further, the docking study revealed that the mono-hydroxylated and terminally desaturated metabolites possess better binding affinity than the parent drug. Therefore, these metabolites may hold sEH inhibition potential and can be followed through future research.

Molecular Insights into the Mechanism of Modulatory Effects of Proton Pump Inhibitors on P-glycoprotein Mediated Drug Transport of Palbociclib and Ribociclib.

BACKGROUND: Palbociclib and ribociclib are substrates of efflux transporter P-glycoprotein which plays a key role in absorption and transport of these drugs. Proton pump inhibitors, when co-administered with them are known to show inhibitory effect on P-glycoprotein. OBJECTIVE: Therefore, this study aims to investigate the role of proton pump inhibitors in inhibition of P-glycoprotein mediated efflux of palbociclib and ribociclib. METHOD: A combined approach of molecular docking and ex vivo everted gut sac model was implemented to predict the potential of proton pump inhibitors i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole to inhibit the P-glycoprotein mediated intestinal transport of palbociclib and ribociclib and study the molecular basis of interaction taking place. RESULTS: Molecular docking studies revealed that omeprazole, rabeprazole and pantoprazole bound to the ATP site of nucleotide binding domain with binding energies of -27.53, -29.56 and -38.44 Kcal/mol respectively. In ex vivo studies, rabeprazole and omeprazole, affected the absorptive permeability of palbociclib by 3.04 and 1.26 and ribociclib by 1.76 and 2.54 folds, respectively. Results of molecular docking studies and ex vivo studies highlighted that proton pump inhibitors bound to the ATP binding site to block its hydrolysis thereby inhibiting the P-glycoprotein mediated efflux of palbociclib and ribociclib. CONCLUSION: The experimental evidence presented highlights the fact that proton pump inhibitors have potential to inhibit P-glycoprotein, giving rise to drug interactions with palbociclib and ribociclib. Hence, monitoring is required while proton pump inhibitors and cyclin-dependent kinase inhibitors are being co-administered to avoid adverse events.

Recent advances in co-amorphous drug formulations.

Co-amorphous drug delivery systems have recently gained considerable interest in the pharmaceutical field because of their potential to improve oral bioavailability of poorly water-soluble drugs through drug dissolution enhancement as a result of the amorphous nature of the material. A co-amorphous system is characterized by the use of only low molecular weight components that are mixed into a homogeneous single-phase co-amorphous blend. The use of only low molecular weight co-formers makes this approach very attractive, as the amount of amorphous stabilizer can be significantly reduced compared with other amorphous stabilization techniques. Because of this, several research groups started to investigate the co-amorphous formulation approach, resulting in an increasing amount of scientific publications over the last few years. This study provides an overview of the co-amorphous field and its recent findings. In particular, we investigate co-amorphous formulations from the viewpoint of solid dispersions, describe their formation and mechanism of stabilization, study their impact on dissolution and in vivo performance and briefly outline the future potentials.