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CacoReady in the Literature

  • In European Pharmaceutical Review’s latest podcast episode, supported by Lonza, Assistant Editor Hannah Balfour discusses all things bioavailability with Dr Deanna Mudie, a Principal Scientist in Research and Development at Lonza’s site in Bend, Oregon, US. “For oral drugs, bioavailability is the fraction of the administered dose that actually reaches your systemic circulation unchanged,” explains Deanna, continuing that it must be high to ensure all or most of the drug can reach its site of action for the best therapeutic effect. She went on to explain how dissolution and solubility both factor into how much drug reaches the circulation and some of the key drug properties that affect them, including particle size and lipophilicity. in vitro dissolution testing has really been the gold standard for helping to assess, not only how quickly, but also to what extent a drug appears in the bloodstream” However, the diverse range of potential medias can be challenging, so Deanna explained Lonza’s three step approach for selecting the right media: determine the testing goal, ascertain the target population of interest (eg, human, canine, etc.) and select the dissolution apparatus and media that represents the key features of the properties that may affect the drug in this species. “When you use a dissolution medium selection approach like this it can be really powerful because it combines the knowledge of key physiological properties with the drug formulation properties… this can enable ‘right first time’ development, reduce the costs and increase the development speed of medicine,” states Deanna. More Info >>>
  • Preliminary in Vitro Assessment of the Potential of EST64454, a Sigma-1 Receptor Antagonist, for Pharmacokinetic Drug–Drug Interactions. Yeste, S., et al. (2020). EST64454 is a selective sigma-1 receptor ligand intended for orally administered pain treatment that showed a promising profile in the lead optimization process. As part of the preliminary compound profiling, the potential for future drug–drug interactions was explored in vitro. Both direct and time-dependent CYP inhibition for CYP1A2, 2C9, 2C19, 2D6 and 3A4 was studied in human liver microsomes. More Info >>>
  • No evidence for interactions of dimethylfumarate (DMF) and its main metabolite monomethylfumarate (MMF) with human cytochrome P450 (CYP) enzymes and the P-glycoprotein (P-gp) drug transporter. Aubets J, Jansat J-M, Salva M, et al. (2019). DMF was not
    a substrate for P-gp (net efflux ratios ≤1.22) but was a weak inhibitor of P-gp at supratherapeutic concentrations (estimated IC50 relative to solvent control of 1.5 mmol/L;[3H]digoxin efflux in Caco-2 cells). This inhibition is unlikely to be clinically relevant. More Info >>>
  • Targeted Covalent Inhibition of Prolyl Oligopeptidase (POP): Discovery of Sulfonylfluoride Peptidomimetics. Guardiola et al. (2018). Prolyl oligopeptidase (POP), a serine protease highly expressed in the brain, has recently emerged as an enticing therapeutic target for the treatment of cognitive and neurodegenerative disorders. Here, we describe that at low-nanomolar concentrations, these covalent peptidomimetics produce a fast, specific, and sustained inactivation of POP, both in vitro and in human cells. More Info >>>