title: Biorelevant media for transport experiments in the Caco-2 model to evaluate drug absorption in the fasted and the fed state and their usefulness.
abstract: In this work we developed and characterized transport media that simulate the composition of micellar phase of intestinal fluids in the fasted and, especially, in the fed state and are appropriate for evaluating intestinal drug permeability characteristics using the Caco-2 model (FaSSIF-TM(Caco) and FeSSIF-TM(Caco), respectively). Media composition was based on FaSSIF-V2 and FeSSIF-V2 and recently reported data on total lipid concentrations in the micellar phase of contents of the upper small intestine in the fasted and the fed state and was adapted for cell culture compatibility. Permeation data were evaluated by compartmental kinetic modeling. Permeability coefficients, P, of hydrophilic drugs were not affected by media composition. In contrast, P values of a series of lipophilic compounds measured with FaSSIF-TM(Caco) and FeSSIF-TM(Caco), and reflecting transport by diffusion were smaller than those obtained with a purely aqueous reference transport medium, aq-TM(Caco), following the rank order aq-TM(Caco)>FaSSIF-TM(Caco)>FeSSIF-TM(Caco). The decline of permeability values was stronger as lipophilicity of the compounds increased. Compared with values estimated using aq-TM(Caco), permeability was reduced, depending on the compound, by more than 20- to 100-fold when measured with FeSSIF-TM(Caco) whereas compound ranking in regard to the permeability characteristics was also affected. The impact of reduced P value on flux through the mucosa, hence on drug absorption, in combination with the drug amount loaded on colloidal particles needs to be taken into consideration in PBPK modeling especially when the food effect is evaluated.
authors.affiliation: Institute of Pharma Technology, University of Applied Sciences Northwestern Switzerland, Switzerland; Laboratory of Biopharmaceutics and Pharmacokinetics, National and Kapodistrian University of Athens, Greece.
authors.forename: C
authors.initials: C
authors.lastname: Markopoulos
authors.affiliation: Institute of Pharma Technology, University of Applied Sciences Northwestern Switzerland, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Thoenen
authors.affiliation: Department of Pharmaceutical Sciences, University of Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Preisig
authors.affiliation: Laboratory of Biopharmaceutics and Pharmacokinetics, National and Kapodistrian University of Athens, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Symillides
authors.affiliation: Laboratory of Biopharmaceutics and Pharmacokinetics, National and Kapodistrian University of Athens, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Vertzoni
authors.affiliation: F. Hoffmann-La Roche, Inc., Basel, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Parrott
authors.affiliation: Laboratory of Biopharmaceutics and Pharmacokinetics, National and Kapodistrian University of Athens, Greece.
authors.forename: C
authors.initials: C
authors.lastname: Reppas
authors.affiliation: Institute of Pharma Technology, University of Applied Sciences Northwestern Switzerland, Switzerland; Department of Pharmaceutical Sciences, University of Basel, Switzerland. Electronic address: georgios.imanidis@unibas.ch.
authors.forename: G
authors.initials: G
authors.lastname: Imanidis
mesh_terms: D001692:Biological Transport / Q000502:physiology; D001826:Body Fluids / Q000737:chemistry / Q000378:metabolism*; D018938:Caco-2 Cells; D017077:Culture Media, Conditioned / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005215:Fasting / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D019518:Postprandial Period / Q000502:physiology*
chemical_list: D017077:Culture Media, Conditioned
keywords: Biorelevant media; Caco-2; Fasted state; Fed state; Intestinal absorption; Permeability coefficient