Differential effects of dietary polyphenols on oral pharmacokinetics of cyclin-dependent kinase inhibitors in rats: a mechanistic framework for in vitro-in vivo extrapolation.

OBJECTIVES: Cyclin-dependent kinase inhibitors are subject to rapid first-pass metabolism, and their oral absorption is hindered by intestinal CYP3A4 and P-gp. The present study investigates the impact of dietary polyphenols on the oral pharmacokinetics of palbociclib and ribociclib, considering their potential as modulators of CYP3A4 and P-gp. METHODS: Therefore, potential inhibitory effects of dietary polyphenols on drug metabolism and efflux of these drugs were investigated using molecular docking; in vitro preclinical assay using rat liver microsomes and Caco-2 cell monolayers; in vivo, pharmacokinetic parameters were determined in rats pretreated with dietary polyphenols. KEY FINDINGS: Curcumin and quercetin have the highest binding affinities to the PXR's AF-2 region cluster. Curcumin and quercetin significantly inhibited both intestinal efflux and CYP3A4-mediated metabolism of palbociclib and ribociclib (P < .05). In rats pretreated with curcumin, Cmax of palbociclib exhibited a 5.13% increase, while the AUC0-24h of ribociclib showed a significant increase of 18.83% (P < .05). Quercetin administration, notably, impedes the pharmacokinetics of palbociclib. However, the pharmacokinetics of ribociclib remains unaffected by quercetin. CONCLUSIONS: In conclusion, the utilization of curcumin as a bioenhancer can enhance the bioavailability of dual substrates of P-gp and CYP3A4.

Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents.

Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy-4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M. tuberculosis H37Rv (MIC = 4-7 µM) and Mycobacterium bovis (% inhibition at 10 µM = 95.91%). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development.

Synthesis of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives under Pd/Cu-catalysis: Identification of potent inhibitors of chorismate mutase (CM).

The chorismate mutase (CM) is considered as an attractive target for the identification of potential antitubercular agents due to its absence in animals but not in bacteria. A series of 3-indolylmethyl substituted pyrazolotriazinone derivatives were designed and docked into CM in silico as potential inhibitors. These compounds were efficiently synthesized using the Pd/Cu-catalyzed coupling-cyclization in a single pot involving the construction of indole ring. The methodology was later extended to the preparation of corresponding benzo analogs of pyrazolotriazinones i.e. 3-indolylmethyl substituted benzotriazinone derivatives. Several of these novel compounds showed significant inhibition of CM when tested in vitro at 30 µM. The SAR (Structure-Activity-Relationship) studies suggested that benzotriazinone moiety was more favorable over the pyrazolotriazinone ring. The two best active compounds showed IC50 ∼ 0.4-0.9 µM (better than the reference/known compounds used) and no toxicity till 30 µM in vitro.

Fabrication, solid state characterization and bioavailability assessment of stable binary amorphous phases of Ritonavir with Quercetin.

In the current study, Quercetin (QRT) was characterized for thermodynamic and kinetic parameters and found as an excellent glass former. QRT was paired with Ritonavir (RTV) (BCS class-IV antiretroviral) to form stable amorphous form and pharmacologically relevant combination. Binary amorphous forms of RTV and QRT in molar ratios 1:1, 1:2 and 2:1 were prepared by solvent evaporation technique and characterized by XRPD, DSC and FTIR. The prepared binary phases were found to become amorphous after solvent evaporation which was confirmed by disappearance of crystalline peaks from X-ray diffractograms and detecting single Tg in DSC studies. The physical stability studies at 40 °C for 90 days found RTV:QRT 1:2 and RTV:QRT 2:1 phases stable, while trace crystallinity was detected for 1:1M ratio. The temperature stability of RTV:QRT 1:2 and RTV:QRT 2:1 amorphous forms can be attributed to phase solubility of both components where the drug in excess acts as a crystallization inhibitor. Except for RTV:QRT 1:2 ratio, there was no evidence of intermolecular interactions between two components. Almost 5 fold increase in the saturation solubility was achieved for RTV, compared to crystalline counterpart. While for QRT, the solubility advantage was not achieved. In vivo oral bioavailability study was conducted for 1:2 binary amorphous form by using pure RTV as a control. Cmax was improved by 1.26 fold and Tmax was decreased by 2h after comparing with control indicating improved absorption. However no significant enhancement of oral bioavailability (1.12 fold after comparing with control) was found for RTV.

Preparation and characterization of co-amorphous Ritonavir-Indomethacin systems by solvent evaporation technique: improved dissolution behavior and physical stability without evidence of intermolecular interactions.

The aim of this study was to stabilize the amorphous form of Ritonavir (RTV) a BCS class-II drug with known amorphous stabilizing small molecule Indomethacin (IND) by co-amorphous technology. The co-amorphous samples were prepared by solvent evaporation technique in the molar ratios RTV:IND (2:1), RTV:IND (1:1), RTV:IND (1:2) and their amorphous nature was confirmed by XRPD, DSC and FT-IR. Physical stability studies were carried out at temp 25°C and 40°C for maximum up to 90 days under dry conditions. Solubility and dissolution testing were carried out to investigate the dissolution advantage of prepared co-amorphous systems. The amorphous mixtures of all tested molar ratios were found to become amorphous after solvent evaporation. The same was confirmed by detecting halo pattern in diffractograms of co-amorphous mixtures. The Tg values of all three systems were found to be more than 40°C, the highest being 51.88°C for RTV:IND (2:1) system. Theoretical Tg values were calculated by Gordon-Taylor equation. Insignificant deviation of theoretical Tg values from that of practical one, corroborated by FT-IR studies showed no evidence of intermolecular interactions between RTV and IND. Almost 3-folds increase in the solubility for both amorphous RTV and IND was found as compared to their respective crystalline counterparts. The study demonstrated significant increase in the dissolution rate as well as increase in the total amount of drug dissolved for amorphous RTV, however it failed to demonstrate any significant improvement in the dissolution behavior of IND.