Evaluation of a novel in vitro Caco-2 hepatocyte hybrid system for predicting in vivo oral bioavailability.
A novel in vitro Caco-2 hepatocyte hybrid system was set up and tested for its ability to predict the oral bioavailability (F) in humans of 24 randomly chosen marketed drugs. Caco-2 cells were cultured on the transwell filters to form tight junctions. Pooled cryopreserved human hepatocytes were placed in the basolateral receiver compartment. To evaluate the permeability and hepatic first pass in one experiment, compounds were dissolved in medium and added to the apical donor compartment of the transwell apparatus, and the amount of the parent compound appearing in the basolateral receiver compartment was determined over a 3-h time course. The area under the concentration versus time curve (AUC) of the parent compound was determined. The predictive usefulness of this Caco-2 hepatocyte model was tested by comparing the AUC with the in vivo oral bioavailability reported in the literature. Linear regression analysis shows a reasonable correlation (R(2) = 0.86) between the in vitro AUC and oral bioavailability reported in the literature. Based on the literature data, the compounds were classified into low (F < 20%), medium (20 < F < 50%), and high (F > 50%) bioavailability categories. The oral bioavailability predicted from the experimental Caco-2 hepatocyte system successfully matches the appropriate literature-based bioavailability category for 22 of 24 of the compounds. The results presented in this study suggest that it may be feasible to combine Caco-2 cells and hepatocytes into one system for the prediction of oral absorption and first-pass effect in humans.
Schering-Plough Research Institute, K-15-2-2700, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Yau Yi
YY
Lau
Yung-Hsiang
YH
Chen
Tong-Tong
TT
Liu
Cheng
C
Li
Xiaoming
X
Cui
Ronald E
RE
White
K-C
KC
Cheng
D000042:Absorption / Q000187:drug effects; D000284:Administration, Oral; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects* / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D010539:Permeability / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000145:classification / Q000378:metabolism
D004364:Pharmaceutical Preparations