Modulation of tight junctions does not predict oral absorption of hydrophilic compounds: use of Caco-2 and Calu-3 cells.
Permeability estimates using Caco-2 cells do not accurately predict the absorption of hydrophilic drugs that are primarily absorbed via the paracellular pathway. The objective of this study was to investigate whether modulation of tight junctions would help differentiation of paracellularly absorbed compounds. Tight junctions in Caco-2 cell monolayers were manipulated using calcium depletion approaches to decrease the transepithelial electrical resistance (TEER) of the monolayers, and permeability of hydrophilic compounds were measured under these conditions. Permeability of these compounds were also measured in Calu-3 cells, which have tighter junctions than Caco-2 cells. Calcium depletion loosened the tight junctions of Caco-2 cells to varying levels as measured by the decrease in TEER values of the monolayers. While the absolute permeability of all the model compounds increased as the tight junctions were loosened, the ratios of their permeability relative to mannitol permeability were similar. The permeability of these compounds in the tighter Calu-3 cells were also found to be similar to each other. Altering the tight junctions of Caco-2 cells to obtain leakier cell monolayers, or using a cell line with tighter junctions like Calu-3 cells, did not improve differentiation between well absorbed and poorly absorbed hydrophilic drugs. Mere manipulation of the tight junctions to increase or decrease transepithelial electrical resistance does not appear to be a viable approach to predict human absorption for hydrophilic compounds that are primarily absorbed via the paracellular pathway.
Kamath
Amrita V
AV
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
Morrison
Richard A
RA
Mathias
Neil R
NR
Dando
Sandra A
SA
Marino
Anthony M
AM
Chong
Saeho
S
D000042:Absorption; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability; D004847:Epithelial Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D009061:Mouth Mucosa / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism* / Q000502:physiology
D004364:Pharmaceutical Preparations; D002118:Calcium