title: Development of in vitro pharmacokinetic screens using Caco-2, human hepatocyte, and Caco-2/human hepatocyte hybrid systems for the prediction of oral bioavailability in humans.
abstract: In this study, in vitro systems were used to build 2 pharmacokinetic models that predict human oral bioavailability: the Caco-2/hepatocyte combination model and the Caco-2/hepatocyte hybrid model. Data obtained in vitro on Caco-2 cell permeability and hepatocyte clearance are routinely used to predict the fraction of absorption after oral administration and the extent of first-pass metabolism, respectively. In the Caco-2/hepatocyte combination model, results from a Caco-2 cell permeability assay and a hepatocyte clearance assay were combined to project oral bioavailability. Comparison of oral bioavailabilities predicted by the combination model and reported oral bioavailabilities in humans for 30 marketed compounds resulted in a modest correlation (r(2) = 0.66). The Caco-2/hepatocyte hybrid model, as previously reported, joins the Caco-2 and hepatocyte clearance systems into 1 assay. Improvements to the previous model were made by incorporating an elimination phase into the Caco-2/hepatocyte hybrid model. In the new hybrid model, the compound was added to a Caco-2-containing donor compartment and allowed to permeate for 2 h to a hepatocyte-containing receiver compartment. Subsequently, to mimic an elimination phase, the donor compartment was removed, and permeated compound was incubated with hepatocytes alone for an additional 3 h. The area under the concentration versus time curve (AUC) was determined for each of the same 30 marketed compounds assessed by the combination model. A linear regression analysis comparing the in vitro AUCs and reported oral bioavailabilities in humans showed a reasonable correlation (r(2) = 0.73). This study demonstrates that the Caco-2/hepatocyte hybrid model is more favorable and further proves the potential and feasibility of using in vitro screenings for the prediction of in vivo pharmacokinetics in humans.
authors.affiliation: Department of Exploratory Drug Metabolism, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Tongtong
authors.initials: T
authors.lastname: Liu
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Cui
authors.forename: Annette S
authors.initials: AS
authors.lastname: Uss
authors.forename: K-C
authors.initials: KC
authors.lastname: Cheng
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics; D012015:Reference Standards; D013997:Time Factors