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Received December 3, 1996; accepted February 10, 1997
KEY WORDS: Ussing chamber; in vitro; in vivo; jejunal permeability.
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INTRODUCTION
Investigation of the transport of systemically acting drugs across the intestinal membranes is fundamental in order to develop strategies such as; (a) improvements of the mass of drug absorbed from the oral product, and (b) biopharmaceutical criterias for selection of the most appropriate candidate drug regarding intestinal absorption in humans. Crucial to rational drug design and development is the access to different intestinal permeability models, but direct comparisons with human data are lacking. Recently technical progress in the development and validation of a new regional human perfusion approach has been made, which is used to study membrane transport of drugs in vivo (1). Therefore, it is now possible to directly compare permeability values obtained in the different in vitro/in situ models with these in vivo human effective permeabilities. Recently, such correlations have been reported for Caco-2 cells and in situ perfusion preparations of the rat jejunum (2,3). However, a direct evaluation of the ability of the Ussing chamber technique to predict permeability values for both passively and carrier-mediated transported drugs in humans has not yet been published. As a consequence, we will directly compare the effective permeability coefficients (Peff) determined in human jejunum (in vivo) and excised jejunal segment from rat (in vitro).
The Peff-value of a drug is a biopharmaceutical variable that is possible to use regardless of the transport mechanism across the mucosal barrier (4). A majority of drugs are transported across the intestinal mucosa by passive diffusion, and is determined by the membrane/lumen partitioning (K) and the membrane diffusion coefficient (Dm) (Peff = K·Dm/[lambda]: "Overton's rule") (5,6). [lambda] represents the transport distance for a molecule across the intestinal cell lining. The general view is that lipophilic compounds are transported by the transcellular pathway, whereas hydrophilic and charged molecules, which have lower Peff due to low K and/or Dm-values, are transported through the water filled space between the epithelial cells, the so called paracellular route (6-9). However, the quantitative importance of drug transport by the paracellular route in vivo has been questioned recently (6,8,10). Instead, the passive transcellular diffusion was suggested to be the dominating...