Development of a high-throughput in vitro assay using a novel Caco-2/rat hepatocyte system for the prediction of oral plasma area under the concentration versus time curve (AUC) in rats.
BACKGROUND
Previously, we have shown that a novel Caco-2/human hepatocyte system is a useful model for the prediction of oral bioavailability in humans. In this study, we attempted to use a similar system in a high-throughput screening mode for the selection of new compound entities (NCE) in drug discovery.


METHODS
A total of 72 compounds randomly selected from three different chemotypes were dosed orally in rats. In vivo plasma area under the concentration versus time curve (AUC) from 0-6 h of the parent compound was determined. The same compounds were also tested in the Caco-2/rat hepatocyte system. In vitro AUC from 0-3 h in the Caco-2 rat hepatocyte system was determined.


RESULTS
The predictive usefulness of the Caco-2/rat hepatocyte system was evaluated by comparing the in vivo plasma AUC and the in vitro AUC. Linear regression analysis showed a reasonable correlation (R2 = 0.5) between the in vivo AUC and the in vitro AUC. Using 0.4 microM h in vivo AUC as a cut-off, compounds were categorized as either low or high AUC. The in vitro AUC successfully matched the corresponding in vivo category for sixty-three out of seventy-two compounds.


CONCLUSIONS
The results presented in this study suggest that the Caco-2/rat hepatocyte system may be used as a high-throughput screen in drug discovery for pharmacokinetic behaviors of compounds in rats.
Cheng
K-C
KC
Schering-Plough Research Institute, K-15-2-2700, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. kuo-chi.cheng@spcorp.com
Li
Cheng
C
Hsieh
Yunsheng
Y
Montgomery
Diana
D
Liu
Tongtong
T
White
Ronald E
RE
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001681:Biological Assay; D018938:Caco-2 Cells; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D016014:Linear Models; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D015262:Xenobiotics / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*
D015262:Xenobiotics