In Vitro and Ex Vivo Investigation of the Impact of Luminal Lipid Phases on Passive Permeability of Lipophilic Small Molecules Using PAMPA

Abstract

Evaluate the impact of luminal micellar phase on passive permeability of five lipophilic (1.9 ≤ clogP ≤ 9.0) small molecules using biorelevant media and evaluate the impact of luminal coarse lipid particles on danazol permeability after oral administration of a triglyceride solution to fed adults using PAMPA. Permeability of carbamazepine, furosemide, danazol, and Compound A was evaluated using Prisma™ HT, FaSSIF-V2, and FeSSIF-V2 in the donor compartment. Compound B could not be tested using Prisma™ HT, due to negligible solubility. Individual intestinal aspirates collected after administration of danazol solution in the olive oil portion of a meal and corresponding micellar phases were subjected to PAMPA. Commercially available Acceptor Sink Buffer was used in all cases. Unlike with furosemide (under constant pH) and Compound B, permeability of carbamazepine, danazol, and Compound A steadily decreased in the presence of increasing micelle concentration of media. Danazol permeability from aspirates was reduced compared to that from micellar phases; fluxes were similar. Using PAMPA, the impact of luminal micellar phase on passive permeability of lipophilic molecules varies with the molecule. After administration of a triglyceride solution of danazol, high danazol concentrations in coarse lipid particles balance in terms of drug flux the reduced permeability.