Intestinal absorption carrier-mediated transport

Tamai, I. [Molecular characterization of intestinal absorption of drugs by carrier-mediated transport mechanisms]. Yakugaku Zasshi 1997, 117, 415-434. 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

Note CLapp,c apparent membrane permeability clearance for carrier-mediated transport component at lower concentrations where it is highly efficient SI, small intestine ileum for taurocholate and midgut for the others. Absorption was evaluated in our laboratory using the closed loop of the rat intestine in situ (urethane anesthesia, 1.125 g/4.5 ml/kg, i.p.) in 60 min for riboflavin and 30 min for the others. 

Note Data represent the mean S.E. (n = 3). MW, molecular weight P0/w, octanol-to-water partition coefficient CLapp, apparent membrane permeability clearance SI, midgut area of the small intestine NA, not available or applicable. Absorption was evaluated in our laboratory using the closed loop of the rat intestine in situ (urethane anesthesia, 1.125 g/4.5 ml/kg, i.p.) in 60 min for riboflavin and L-camitine and 30 min for the others. For those that are transported by carriers in part (riboflavin and glycerol in both colon and SI, and L-carnitine, 5-fluorouracil, and cephradine in SI), absorption was evaluated at higher concentrations where the contribution of carrier-mediated transport is negligible. Values of P0/w were obtained from a report by Leo et al. [30] except for that of D-xylose, which was determined in our laboratory. a Data by single-pass perfusion experiments. b Unpublished data from our laboratory. 

In addition to screening molecules for intestinal absorption, Caco-2 cells have also been used to study mechanisms of drug transport. For many compounds, intestinal permeation involves a transporter to either aid or limit transepithelial transport. The value of Caco-2 cells in this type of studies is due to the fact that these cells express various membrane transporters relevant to drug absorption.1719-23,28,30 However, when interpreting results of studies that involve carrier-mediated transport, discretion, and scaling factors may be required because of the difference in expression level of transporters between in vitro and in vivo systems.12 Another important consideration in carrier-mediated transport studies is that some transport systems in Caco-2 cells may achieve maximal expression level at different days in culture.17,21,38,74 Thus, validation of Caco-2 cells for mechanistic studies should include the identification of the time for optimal expression of transporters as well as the qualitative evaluation of the transporters to establish that they are representative of the native intestinal transporters. 

Boundary layers also contribute to the effect of intestinal fluid hydrodynamics on drug absorption by both diffusional- and carrier-mediated processes. In a well-defined isolated in situ model such as perfused intestine of the rat, a good estimate of the gut wall permeability, which is the vector of convective diffusive mass transfer, passive diffusion and carrier-mediated transport, can be accomplished [99,100]. 

Mizuma, T., et al. 2005. Intestinal SGLT1-mediated absorption and metabolism of benzyl beta-glucoside contained in Prunus mume Carrier-mediated transport increases intestinal availability. Biochim Biophys Acta 1722 218. 

Other transcellular mechanisms of absorption include carrier-mediated transport and endocytic processes. Although it is well known that carrier-mediated transport systems exist for di- and tripeptides in the intestine, there is still no evidence for carrier-mediated transport of peptides across the vaginal mucosa, although prostaglandins have been demonstrated to utilize such a mechanism. Although there must be some type of endocytic transport of endogenous peptides into the epithelial cells in order to regulate proliferation, no receptor-mediated or bulk-fluid mechanisms have been reported. 

The studies reported here using the isolated, vascularly perfused rat intestine system and isolated brush border membrane vesicles fail to support a role for a specific zinc-binding ligand involved in zinc uptake in the rat. Rather, the extent of zinc uptake involves the interaction of several phenomena, including both extracellular and intracellular reactions. It appears that the major pathway of zinc uptake under normal dietary conditions involves the transfer of zinc from various dietary components to a carrier mediated transport system at the brush border membrane. The net absorption of zinc from the lumen could involve a competition between various dietary components, zinc binding ligands and the membrane carrier for zinc. Thus, in some cases, those compounds in the lumen with a higher affinity for zinc than the membrane component will be less likely to permit transfer of zinc to the carrier, while compounds with a lower affinity for zinc will increase the amount of zinc made... 

Theoretically, a lipophilic drug may pass through the cell or go around it. If drug has a low molecular weight and is lipophilic, the lipid cell membrane is not a barrier to drug diffusion and absorption. In the intestine, molecules smaller than 500 MW may be absorbed by paracellular drug absorption. Numerous specialized carrier-mediated transport systems are present in the body especially in the intestine for the absorption of ions and nutrients required by the body. 

Figure 4.8 Schematic drawing of the mechanisms and routes of drug absorption across intestinal epithelia. Drugs can be absorbed transcellularly [1) and paracellularly (2) by passive diffusion or transcellularly via carrier-mediated transport [3) or endocytosis C4). Enzymes in the brush-border region or intracellular enzymes and the efflux proteins, e.g., P-glycoprotein (5) contribute to the elimination of harmful compounds.

The second method in this group is the intestinal rings or slices. This method for studying drug absorption has been used extensively for kinetic analysis of carrier-mediated transport of glucose, amino acids and peptides (Kararli 1989 Osiecka et al. 1985 Porter et al. 1985 Kim et al. 1994 Leppert and Fix 1994). The method is easy to use the intestine of the animal is cut... 

The absorption of dietary zinc occurs over the duodenal and jejunal regions of the gastrointestinal tract, and mainly follows via a saturable carrier-mediated transport process (Zapsalis and Beck 1985, Lee et al. 1989). The mechanism and control of zinc absorption from the intestine has not yet been fully elucidated, although absorption of zinc is known to be regulated homeostatically, mainly under the control of pancreatic and intestinal secretion and fecal excretion. Homeostasis may involve metal-binding proteins such as metallothionein and cysteine-rich intestinal protein. Metallothionein plays an essential role in the regulation of zinc metabolism (Richard and Cousins 1975, Petering and Fowler 1986). Other unknown mechanisms may also exist, and the uptake from intestinal mucosa may involve both active and passive transport processes. 

Figure 9.2 Possible pathways for intestinal absorption of a compound (a) transcellular passive diffusion (b) carrier-mediated transport (c) paracellular absorption (d) entry limited by P-gp, an efflux transporter ...

Single-pass intestinal perfusion studies For evaluatton of intestinal prermeability and lymphatic uptake Predict the exact mechanism of absorption, that is, passive absorption, carrier mediated absorption or active transport Evaluate the P-gp efflux and role of transporters (MRP, BCRP2) in reducing the oral bioavailability of drugs... 

Water-soluble vitamins are believed to be absorbed both by simple diffusion and by carrier-mediated transport, which is sodium-dependent, dtamin 65 is absorbed by passive diffusion, mainly in the small intestine, and the amount absorbed is related linearly to the amount in the digesta.The importance of a carrier glycoprotein (intrinsic factor) for the absorption of vitamin B12 has already been stressed (see p. 98). 

The intestinal absorption of intact peptides or proteins occurs to var3dng extents (Gardner, 1984 Silk et al, 1985 Humphrey and Ringrose, 1986) and generally involves either a passive mechanism, some type of carrier-mediated transport, or receptor-mediated or non-receptor-m iated endocytotic transport. Each mechanism will contribute to the absorption of a peptide or protein to a different degree, depending upon such characteristics as the size, charge, or lipophilicity of the peptide or protein. 

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