Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers

Abstract

Transient permeability enhancers (PEs), such as caprylate, caprate, and salcaprozate sodium (SNAC), improve the bioavailability of poorly permeable macromolecular drugs. However, the effects are variable across individuals and classes of macromolecular drugs and biologics. Here, we examined the influence of bile compositions on the ability of membrane incorporation of three transient PEs—caprylate, caprate, and SNAC—using coarse-grained molecular dynamics (CG-MD). The availability of free PE monomers, which are important near the absorption site, to become incorporated into the membrane was higher in fasted-state fluids than that in fed-state fluids. The simulations also showed that transmembrane perturbation, i.e ., insertion of PEs into the membrane, is a key mechanism by which caprylate and caprate increase permeability. In contrast, SNAC was mainly adsorbed onto the membrane surface, indicating a different mode of action. Membrane incorporation of caprylate and caprate was also influenced by bile composition, with more incorporation into fasted- than fed-state fluids. The simulations of transient PE interaction with membranes were further evaluated using two experimental techniques: the quartz crystal microbalance with dissipation technique and total internal reflection fluorescence microscopy. The experimental results were in good agreement with the computational simulations. Finally, the kinetics of membrane insertion was studied with CG-MD. Variation in micelle composition affected the insertion rates of caprate monomer insertion and expulsion from the micelle surface. In conclusion, this study suggests that the bile composition and the luminal composition of the intestinal fluid are important factors contributing to the interindividual variability in the absorption of macromolecular drugs administered with transient PEs.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Methanol [274,413,414], Ethanol [149,242,284,387,[414][415][416][417][418][419][420], Propanol [414,421], Isopropanol [284], Buthanol [414,417,422], Caprate [423], Glycerol [424], Isopropanol [416],…”

“…Thymol [425] Natural polymers Lignin [426][427][428], Polyphenols [429], Cellulose [430,431], Polysialic acid [432] Gabaergic ketones Carvone, Menthone, Pulegone, Dihydrocarvone, Thujone [433] Taste and aroma Menthol [342,434], Terpenoids [435], Coumarin [132,284,436,437], Limonene [132], 4-ethylphenol (wine/beer aroma) [406], Tannins (wine) [438], Catechin [282] Caffeine and its derivatives Caffeine [132,439], Rosmarinic acid [440][441][442], Caffeic acid [441,443], Chlorogenic acid [441], Paraxanthine [132], Caffeic acid derivatives [444] Pigments Violacein [445,446], Marennine [447] Bile salts [280,423,448] Steroids Betulin [449], Saponins [450,451], Glycyrrhizic acid (saponin) [252,452,453], Withaferin-A and Withanone [454] Lipids N-arachidonylglycine and oleoyl-L-carnitine [137]...…”

Investigation of Self-Emulsifying Drug-Delivery System Interaction with a Biomimetic Membrane under Conditions Relevant to the Small Intestine

“…The exact mechanism of this interaction is not clear, but it is expected that colloidal rearrangement alters the exchange of lipid monomers between the adsorbed membrane and the lipid colloids solubilized within the aqueous media. 51 …”

“…This dynamic equilibrium is expected to be dependent on lipolysis kinetics and colloidal self-assembly because changes in the composition and structure of lipid colloids alter the expulsion dynamics of individual lipid monomers. 51 …”

Transient Permeation Enhancer® (TPE®) technology for oral delivery of octreotide: a technological evaluation

“…Studies using Caco-2 monolayers also indicated that C 8 is far less efficacious as a PE for paracellular marker molecules compared to C 10 [42]. The low efficacy and potency of C 8 are likely due to its reduced propensity to partition into enterocyte plasma membrane lipid bilayers compared to C 10 [43]. There is a counter-argument offered to suggest that C 8 may be effective as a PE because its higher critical micellar concentration (CMC) favors the presence of high concentrations of the active monomeric form in the GI lumen compared to longer chain fatty acids.…”