Physiological Pharmaceutics

128 Physiological Pharmaceuticsgradient for hydrocortisone but not for triamcinolone 46 . Digoxin 47 and hydrochlorthiazide 38have also been shown to be absorbed predominantly from the duodenum and upperjejunum. Although there is excellent absorption from the duodenum, transit through thisarea is extremely rapid, in the order of seconds 16 and hence the actual amount of drugabsorbed from this region will be small.Cell monolayers formed from the human colon cancer cell line Caco-2 have been widelyused to study the absorption of drugs 48 . Caco-2 cells form confluent and polarized monolayerswhen maintained in culture and differentiate towards the mature small bowel enterocytephenotype. Caco-2 cell monolayers mimic intestinal absorptive epithelium and represent avery useful tool for studying transepithelial drug transport. However, some enzymes andtransport systems are expressed to a lesser extent in Caco-2 cells compared to normalenterocytes 49 . Caco-2 cells also express various cytochrome P450 isoforms and phase IIenzymes such as UDP-glucuronosyltransferases, sulphotransferases and glutathione-Stransferases,and hence they have been used study presystemic drug metabolism 50 .Specific carriers for the transport of riboflavin and iron are found principally in theduodenum and jejunum, whereas carriers for bile acid and vitamin B 12are found mainly inthe ileum. The acid microclimate is less obvious in the ileum, favouring the absorption ofweak bases while discouraging the absorption of weak acids. Finally, the ileum containsmore commensal bacteria than the duodenum and jejunum. In elderly subjects, the bacterialpopulation in the ileum may be high enough to metabolize certain drugs thereby reducingtheir efficacy.Absorption and delivery of macromoleculesIt is generally accepted that macromolecules, particularly food proteins, do cross the maturesmall intestinal epithelium in small amounts and reach the systemic circulation. Thepotential as delivery route for orally administered macromolecular drugs including proteinsis being widely explored 51 . There have been several studies on the mechanism and substratestructure-affinity relationship for this transport system. Rapid progress has been maderecently in studies on the molecular basis of the intestinal peptide transport system. Aprotein apparently involved in peptide transport has been isolated from rabbit smallintestine, and genes for human intestinal peptide transporters have been cloned, sequencedand functionally expressed 52 . The cellular uptake of small peptides such as di-, tri- andtetrapeptides and peptidomimetic drugs proceeds via specialized proton-coupledtransporters 53 . The proton-dependent uptake at the apical cell membrane of the enterocytesresults in subsequent exit of intact di- or tri-peptides across the basolateral membrane or,alternatively, intracellular hydrolysis and exit of component amino acids across thebasolateral membrane 54 . The peptide carrier has a broad substrate specificity.Lectins are resistant to digestion and binding to brush-border membranes, henceappreciable amounts of lectins and/or toxins of the general structure of A (toxin)-B (lectin),either free or included in liposomes, may be taken up by and transported through theepithelial cells of the small intestine. As a result tomato lectins have been explored aspotential drug delivery agents 55 .Various strategies have been used to target vaccine antigens to the gut-associatedlymphoid tissues, such as microspheres prepared from various polymers. Certainly in micethe size of the microspheres has to be less than 5 µm for them to be transported withinmacrophages through the efferent lymphatics 56 . Transcytosis through Peyer’s patches ismost suited for highly potent compounds since there are a limited number of Peyer’spatches, hence the overall surface area is relatively small. Patch tissue is rich in lymphocytes,thus substances which interact with lymphocytes are best targeted to Peyer’s patches whenusing the oral route 57 .