Passive transepithelial absorption of thyrotropin-releasing hormone (TRH) via a paracellular route in cultured intestinal and renal epithelial cell lines.
Transport studies using intestinal brush-border membrane vesicles isolated from rats and rabbits have failed to demonstrate proton- or Na(+)-dependent carrier-mediated transport of thyrotropin-releasing hormone (TRH), despite a pharmacologically relevant oral bioavailability. To examine the hypothesis that reported levels of oral bioavailability reflect predominantly a paracellular rather than transcellular route for transepithelial transport of TRH, we have studied TRH transport in cultured epithelial cell types of intestinal (Caco-2 and T84) and renal (MDCK I, MDCK II, and LLC-PK1) origin, whose paracellular pathways span the range of permeability values observed in natural epithelia. Transport of TRH across monolayers of intestinal Caco-2 cells was similar to the flux of mannitol (approximately 1-4% per 4 hr), and unlike other putative substrates for the di-/tripeptide carrier, apical-to-basolateral transport was not increased by the presence of an acidic pH in the apical chamber. TRH transport did not show saturation, being uneffected in the presence of 20 mM cold TRH. In each cell type studied TRH and mannitol transport were similar and positively correlated with the conductance of the cell layers, consistent with a passive mechanism of absorption. This evidence suggests that, providing that a peptide is resistant to luminal hydrolysis, small but pharmacologically significant amounts of peptide absorption may be achieved by passive absorption across a paracellular route.
Thwaites
D T
DT
Gastrointestinal Drug Delivery Research Centre, University of Newcastle upon Tyne, U.K.
Hirst
B H
BH
Simmons
N L
NL
D000042:Absorption; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D008353:Mannitol / Q000493:pharmacokinetics; D012044:Regression Analysis; D013973:Thyrotropin-Releasing Hormone / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured
D008353:Mannitol; D013973:Thyrotropin-Releasing Hormone