A theory of molecular absorption from the small intestine

A theory of molecular absorption from the small intestine is outlined on th e basis of macrotransport analysis. Certain features of the transport proce ss that have not been previously considered in the literature are quantitat ively described. These include complex interrelationships between lumen and membrane diffusion, convection, degradation and absorption mechanisms - an d overall axial convection, dispersion, degradation and absorption rates. T herapeutic molecules are assumed to be introduced in the form of a bolus in to the duodenum. They subsequently convect and diffuse through the duodenum ,jejunum, and ileum. Absorption:into the systemic circulation across the ep ithelial barrier, as well as possible degradation or aggregation in the lum en or at the apical epithelial membrane, contribute to the disappearance of the therapeutic as the bolus travels through the lumen in an oral to cauda l direction. Space- and time-varying lumen concentrations are predicted, as are time-varying systemic concentrations following introduction of the bol us. The inputs to the model are primarily anatomical or physicochemical cha racteristics that are either known or can be measured for a given therapeut ic and animal model. A detailed parametric study is made, elucidating the i ndividual roles of permeability and degradation rates. This leads to a simp le paradigm for determining the two unknowns of the model (the membrane per meability and degradation rate constant) from systemic absorption data; it is shown that the membrane permeability constant can alternatively be estim ated by independent in vitro measurements. Comparisons with published exper imental systemic concentrations are made for molecules ranging from small l ipophilic substances, such as ibuprofen, to polypeptides, such as calcitoni n,and proteins, such as insulin. The deduced epithelial permeability values show reasonable agreement with values determined using alveolar epithelia and Caco-2 cell monolayers. By contrast, the membrane permeability values d educed from a simplified model of absorption from the small intestine show relatively poor agreement with experimental values. The model may be useful as numerical simulation tool for predicting (estimates of) oral dose-respo nse relationships in animals and humans given relatively limited in vivo da ta. (C) 1999 Elsevier Science Ltd. All rights reserved.