CORRELATION BETWEEN ORAL-DRUG ABSORPTION IN HUMANS, AND APPARENT DRUGPERMEABILITY IN TC-7 CELLS, A HUMAN EPITHELIAL INTESTINAL-CELL LINE -COMPARISON WITH THE PARENTAL CACO-2 CELL-LINE

Purpose. To determine and compare the relationship between in vivo ora l absorption in humans and the apparent permeability coefficients (P-a pp) obtained in vitro on two human intestinal epithelial cell lines, t he parental Caco-2 and the TC-7 clone. Methods. Both cell lines were g rown for 5-35 days on tissue culture-treated inserts. Cell monolayers were analysed for their morphology by transmission electron micrograph y, and for their integrity with respect to transepithelial electrical resistance, mannitol and PEG-4000 transport, and cyclosporin efflux. P -app were determined for 20 compounds exhibiting large differences in chemical structure, molecular weight, transport mechanisms, and percen tage of absorption in humans. Results. The TC-7 clone exhibits morphol ogical characteristics similar to those of the parental Caco-2 cell li ne, concerning apical brush border, microvilli, tight junctions and po larisation of the cell line. The TC-7 clone however appeared more homo genous in terms of cell size. Both cell lines achieved a similar monol ayer integrity towards mannitol and PEG-4000. Monolayer integrity was achieved earlier for the TC-7 clone, mainly due to its shorter doublin g time, i.e. 26 versus 30 hours for parental Caco-2 cells. When using cyclosporin A as a P-glycoprotein substrate, active efflux was lower i n the TC-7 clone than in the parental Caco-2 cells. The P-app and mech anisms of transport (paracellular or transcellular routes, passive dif fusion and active transport) were determined for 20 drugs. A relations hip was established between the in vivo oral absorption in humans and P-app values, allowing to determine a threshold value for P-app of 2 1 0(-6) cm/sec, above for which a 100% oral absorption could be expected in humans. Both correlation curves obtained with the two cell types, were almost completely superimposable. These studies also confirmed th at the dipeptide transporter is underexpressed in both cell lines. Con clusions. On the basis of morphological parameters, biochemical activi ty and drug transport characteristics, the TC-7 clone appeared to be a valuable alternative to the use of parental Caco-2 cells for drug abs orption studies.