Celastrol (CST) is a promising natural drug of herbal origin that gained a great interest in the recent years by virtue of its wide variety of pharmacological actions. Nowadays, CST is extensively studied as a natural anticancer surrogate with a potential activity against various types of cancers. However, CST suffers from many limitations that handicapped its clinical utility such as limited aqueous solubility and poor gastrointestinal absorption which resulted into its low oral bioavailability. This work spotlights, for the first time, development of self-assembled phytosomal nanocarriers (CST-PHY) for improving CST solubility and oral bioavailability. First CST-phospholipid complex was prepared by a simple solvent evaporation technique. Formation of CST-phospholipid complex was confirmed by differential scanning calorimetry (DSC), infrared spectroscopy (IR), powder X-ray diffraction (XRD) and partition coefficient determination. After dispersion into deionized water, CST-phospholipid complex was self-assembled to form CST-PHY. The optimized CST-PHY demonstrated a nanometric particle size of 178.4±7.07nm and a negative zeta potential of -38.7±3.61mV. Comparative in-vitro release study showed the ability of phytosomes to significantly enhance CST release compared with crude drug and physical mixture. Pharmacokinetic studies in rabbits revealed significant improvement in CST-PHY oral bioavailability compared with crude CST evidenced by 4-fold increase in AUC and 5-fold increase in C of CST-PHY compared with crude CST. Conclusively, the results confirmed the potential of phytosomal nanocarriers to improve CST oral delivery paving the way for its use for oral cancer therapy.
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http://dx.doi.org/10.1016/j.ijpharm.2017.10.053 | DOI Listing |
J Med Chem
January 2025
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (), and results of a comprehensive comparative study with analogues containing alternative CRBN-directing warheads.
View Article and Find Full Text PDFClin Pharmacokinet
January 2025
Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
Background And Objective: Psilocybin is currently being extensively studied as a potential therapeutic agent for multiple psychiatric disorders. Here, a systematic literature review of all published pharmacokinetic data on the pharmacologically active metabolite of psilocybin, psilocin, is presented.
Methods: The review includes clinical studies that reported pharmacokinetic data and/or parameters after psilocybin administration in humans.
CPT Pharmacometrics Syst Pharmacol
January 2025
Pfizer Inc., Paris, France.
Ritlecitinib is an orally bioavailable, small molecule that has been approved by the U.S. Food and Drug Administration (FDA) as a once-daily oral treatment option for people 12 years of age and older with severe alopecia areata.
View Article and Find Full Text PDFProkinetic agents are drugs used to enhance gastrointestinal motility and treat disorders such as Gastroesophageal Reflux Disease (GERD) and gastroparesis. pH-dependent release systems offer targeted drug delivery, allowing prokinetic agents to be released specifically in desired regions of the gastrointestinal tract. This optimizes drug efficacy and minimizes systemic side effects.
View Article and Find Full Text PDFMol Pharm
January 2025
Department of Pharmacy, National and Kapodistrian University of Athens, Zografou 15771, Greece.
The simulation of antral conditions for estimating drug apparent equilibrium solubility after a high-calorie, high-fat meal is challenging. In this study, (1) we measured the apparent equilibrium solubility of two model lipophilic drugs, ketoconazole and danazol, in antral aspirates collected at various time points after a minced high-calorie, high-fat meal and a glass of water 30 min after initiation of meal administration, and we designated one point estimate for ketoconazole and one point estimate for danazol; (2) we evaluated the usefulness of FeSSGF-V2 and FEDGAS pH = 3 in reproducing the two point estimates; (3) we evaluated potential compositions of FeSSGF-V3 that simulate the pH, the buffer capacity toward both less acidic and more acidic values, and the antral lipid and protein contents with easily accessible, commercially available products, and (4) we identified the most useful composition of FeSSGF-V3 for reproducing the two point estimates. For both model drugs, apparent solubility in FeSSGF-V2 and in FEDGAS pH 3 deviated substantially from the corresponding point estimate.
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