In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man--fact or myth.

PURPOSE

To evaluate and optimize the use of Caco-2 cell monolayers to predict the in vivo absorption of a broad range of compounds in man.

METHODS

Caco-2 cells are derived from human adenocarcinoma colon cells and spontaneously differentiate when grown on porous polyethylene terephthalate membranes (PETP) in a 12 well format to form monolayers of polarized cells possessing function similar to intestinal enterocytes. Transport experiments were conducted using 21 day cultured cells in a shaking water bath at 37 degrees C. Radiolabeled mannitol was used to determine monolayer integrity. Apparent permeability coefficient (Papp) was calculated from the appearance of drug in the receiver side.

RESULTS

A strong correlation was observed between in vivo human absorption and in vitro Papp for a variety of compounds (R = 0.95, N = 35). For compounds that are substrates of p-glycoprotein (Pgp), use of a Pgp inhibitor resulted in a better estimate of absorption in humans. The results of this study suggest that the overall ranking of compounds with Papp < 1 x 10(-6) cm/sec, between 1-10 x 10(-5) cm/ sec, and > 10 x 10(-6) cm/sec can be classified as poorly (0-20%), moderately (20-70%) and well (70-100%) absorbed compounds, respectively.

CONCLUSIONS

These data suggest that Caco-2 cells developed under the culturing and transport conditions defined herein can be used to predict in vivo human absorption of compounds regardless of transport mechanism, viz., transcellular, paracellular and carrier-mediated.