Receptor-mediated transporters

W. J. Chang, K. G. Rothberg, B. A. Kamen, and R. G. Anderson. Lowering the cholesterol content of MA104 cells inhibits receptor-mediated transport of folate. J. Cell Biol. 118 63-69 (1992). 

Fig. 1. Overview of intravascular heme catabolism. Hemoglobin, myoglobin, and other heme proteins are released into the circulation upon cellular destruction, and the heme moiety is oxidized by O2 to the ferric form (e.g., methemoglobin and metmyoglobin). Haptoglobin can bind a substantial amount of hemoglobin, but is readily depleted. Ferric heme dissociates from globin and can be bound by albumin or more avidly by hemopexin. Hemopexin removes heme from the circulation by a receptor-mediated transport mechanism, and once inside the ceU heme is transported to heme oxygenase for catabolism.

Hepatocytes are the dominant cell type in the Hver constituting approx. 70% of all hver cells. They are responsible for the uptake of substances from the blood and for the excretion by the bihary system. Specific requirements have to be met by compounds to be able to enter the hepatocytes. These are definite ranges of molecular weight, lipophiHcity and polarity or charge. Additionally, receptor-mediated transport systems of the hepatocytes pose further requirements on the structure of the substance. 

Bi2 are only about 2 meg, it would take about 5 years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if Bi2 absorption were stopped. Vitamin B12 in physiologic amounts is absorbed only after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa. Intrinsic factor combines with the vitamin Bi2 that is liberated from dietary sources in the stomach and duodenum, and the intrinsic factor-vitamin Bi2 complex is subsequently absorbed in the distal ileum by a highly selective receptor-mediated transport system. Vitamin Bi2 deficiency in humans most often results from malabsorption of vitamin B12 due either to lack of intrinsic factor or to loss or malfunction of the specific absorptive mechanism in the distal ileum. Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products. 

Receptor-mediated transporters are excipients that serve as substrates to exploit specific receptors present on cell membranes. Examples of various receptors that have been explored for permeation enhancement include bile acids (45), vitamin Bi2 (46), amino acids (47), and folic acid (48). Most of the work in receptor-mediated transporters is conducted via the use of prodrugs. For example, a prodrug of acyclovir conjugated to bile acids was seen to have higher permeability as compared to the original drug, because of receptor-mediated transport of the prodrug via bile acid transporters (49). 

The pathways of drug absorption are transcellular and paracellular. Moreover, absorption can be due to the vesicular- or receptor-mediated transport or it can occur through the aqueous pores on the mucosa surface. 

Talkuder, J.R., T. Takeuchi, and E. Harada. 2003. Receptor-mediated transport of lactoferrin into the cerebrospinal fluid via plasma in young calves. J Vet Med Sci 65 957. 

Design of ligand-bound macromolecules for receptor-mediated transport. 

Swaan, P. W. Recent advances in intestinal macromolecular drug delivery via receptor-mediated transport pathways. Pharm. Res. 15 826-834, 1998. 

It has been shown that antibodies can reach the systemic circulation after oral administration, but only to a very small extent. The antibodies pass the intestinal epithelium not by passive transcellular but by receptor-mediated transcellular or paracellular transport. The Fc part of the antibody is responsible for the saturable receptor-mediated transport, especially IgG in breast-fed neonates. As the receptor is found primarily in the gastrointestinal tract of neonates, it was called Fc-Rn (Fc receptor neonatal). Apart from this location, Fc-Rn has also been discovered in other tissues such as the liver. Its role will be further discussed in Section 3.9.3. 

Urayama, A., Grubb, J. H., Sly, W. S. and Banks, W. A. (2004). Developmen-tally regulated mannose 6-phosphate receptor-mediated transport of a... 

G. E. King and S. M. Johnson. Receptor-mediated transport of insulin across endothelial cells. Science 277 1583-1588 (1985). 

In epithelium, cytosolic or non-receptor-mediated transport is inefficient and often leads to lysosomal degradation of the macromolecule [109], However, macromolecules, including IgG, are readily transported across the mesothelial surface of the peritoneum. The mesothelial lining cells are flat cells with pino-cytotic vesicles but no caveolae comparable to endothelial cells [193], Gap junctions separate interdigitated peritoneal mesothelial cells. IgG transport is known to be bi-directional and passive in rats [194-198] and also occurs in chronic peritoneal dialysis in humans [199],... 

In healthy individuals lysosomal enzymes are transported from the endoplasmic reticulum to the lysosome via mannose-6-phosphate (M6P) mediated vesicles or other receptor-mediated transporters [5]. The phosphate-labeled enzyme in the case of M6P-mediated transport is released to the lysosome by... 

Urayama A, Grubb JH, Sly WS, Banks WA (2004) Developmentally regulated mannose 6- phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain banier. Proc Natl Acad Sci USA 101 12663. 

ROLE OF TRANSPORT PROCESSES AT THE BLOOD-BRAIN BARRIER RECEPTOR-MEDIATED TRANSPORT OF DRUGS... 

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