Drug-Induced Dynamics of Bile Colloids

Abstract

Bile colloids containing taurocholate and lecithin are essential for the solubilization of hydrophobic molecules including poorly water-soluble drugs such as Perphenazine. We detail the impact of Perphenazine concentrations on taurocholate/lecithin colloids using analytical ultracentrifugation, dynamic light scattering, small-angle neutron scattering, nuclear magnetic resonance spectroscopy, coarse-grained molecular dynamics simulations, and isothermal titration calorimetry. Perphenazine impacted colloidal molecular arrangement, structure, and binding thermodynamics in a concentration-dependent manner. At low concentration, Perphenazine was integrated into stable and large taurocholate/lecithin colloids and close to lecithin. Integration of Perphenazine into these colloids was exothermic. At higher Perphenazine concentration, the taurocholate/lecithin colloids had an approximately 5-fold reduction in apparent hydrodynamic size, heat release was less exothermic upon drug integration into the colloids, and Perphenazine interacted with both lecithin and taurocholate. In addition, Perphenazine induced a morphological transition from vesicles to wormlike micelles as indicated by neutron scattering. Despite these surprising colloidal dynamics, these natural colloids successfully ensured stable relative amounts of free Perphenazine throughout the entire drug concentration range tested here. Future studies are required to further detail these findings both on a molecular structural basis and in terms of in vivo relevance.

Predicting Bile and Lipid Interaction for Drug Substances

“…We referenced all drugs to the 1 H NMR signal shifts seen for Metoprolol’s aryl-proton signals. Metoprolol is a bile noninteracting and lipid noninteracting molecule. , Based on these Metoprolol experiments, a drug’s mean aryl-proton signal shift exceeding 8 Hz in the presence and absence of TC/L, respectively, classified it as bile-interacting (Table ). Drugs with no signals in PBS (e.g., solubility constraints; signal to noise ratio < 10) but in TC/L were classified as bile-interacting.…”

“…1 H NMR signal shifts and intensity changes were analyzed for 141 drugs in PBS, in the presence of TC/L, and TC/L with lipids, and six patterns were differentiated classifying drugs into TC/L and lipid interacting (Figure and Tables S1 and ). ,, Within patterns 4 and 6, mainly poorly water-soluble class II and IV drugs according to the biopharmaceutical classification system were found (Figures S3 and S4). QSPR models using molecular descriptors decoded the molecular requirements for drugs interacting with TC/L and lipids (Figures and and Table S3), and prediction models were developed (Tables and and Figure ).…”

“…All drugs were systematically classified as bile or lipid interacting or noninteracting using the 1 H NMR shifts of Metoprolol for reference. Metoprolol was previously characterized as not interacting with TC/L or lipids. , The classification led to molecular descriptors and models for predicting TC/L and lipid interaction. The bile interaction model was further tested for predicting bile-related food effects.…”

“…Metoprolol was previously characterized as not interacting with TC/L or lipids. 13,26 The classification led to molecular descriptors and models for predicting TC/L and lipid interaction. The bile interaction model was further tested for predicting bile-related food effects.…”

Concentration and Composition Dependent Aggregation of Pluronic- and Poly-(2-Oxazolin)-Efavirenz Formulations in Biorelevant Media

“…[42] Other studies could show the effect of drug concentration on the colloidal aggregates within the intestinal fluids. [43]This underlines the need for thorough investigations of complex mixtures of DDS in biorelevant media to gain a better understanding and an improved predictability of the in vivo behaviour. [44] Previous studies relied on flux measurements of polymeric drug formulations across artificial membranes in combination with differential scanning calorimetry (DSC).…”