Receptor-mediated clearance

The principal organs involved in the peripheral clearance of hGH from the plasma are the kidney and fiver. hGH is cleared via glomerular filtration at the kidney and by a receptor-mediated mechanism at the fiver (58,59). In animal models, derivatives of hGH such as the 20,000 mol wt variant, oligomeric forms, and hGH complexed with GH-binding protein have been shown to be cleared from the semm at significandy lower rates than 22,000 mol wt hGH (60—62). The prolonged plasma half-life of these derivatives probably reflects a combination of decreased receptor affinity and size constraints on glomerular filtration. 

IgG autoantibody-coated platelets induce Fey receptor-mediated phagocytosis by mononuclear macrophages, predominantly in the spleen and liver. Thrombocytopenia develops as a consequence of megakaryocyte inability to increase platelet production and maintain a normal number of circulating platelets. Currently used treatments are directed at different aspects of the antibody production, platelet sensitization, and the clearance and production cycle.30... 

Bartl, MM, Luckenbach, T, Bergner, O, Ullrich, O, and Koch-Brandt, C, 2001. Multiple receptors mediate apoJ-dependent clearance of cellular debris into nonprofessional phagocytes. Exp Cell Res 111, 130-141. 

As already indicated, inherited abnormalities (FDB) or inherited absence of apo-B100 abetalipoproteinemia (ABL) can influence the plasma concentration of Lp(a) and apo(a). In the first case, some investigators indicated an increased concentration of Lp(a) that could not be explained by a defective clearance through LDL-receptor-mediated processes (P8). Other investigators did not find any increase of Lp(a) in FDB at all (HI5). 

In patients clearance of intravenous heme is rapid until hemopexin levels are depleted (148), and lack of interaction with hemopexin may explain the higher clinical efficacy of heme-arginate compared with hemin itself (149, 150). In intact animals, i.v. heme causes rapid association of hemopexin but not albumin with the liver (47, 63, 68), and heme uptake from heme-albumin complexes into isolated rat hepato-cytes occurs via diffusion of heme released from its loose complex with BSA (137). Moreover, unlike uptake from heme-hemopexin, free heme uptake by cells occurred even at 4°C, as expected for nonspecific membrane association and in total disagreement with a membrane-receptor-mediated or active transport uptake process. 

Targeting to SECs should be directed at specific receptors present on this ceU type. A wide range of proteins and other molecules can be taken up by SECs through receptor-mediated endocytosis. For example, SECs play an important role in the uptake of degradation prodncts of the extracellular matrix. For this purpose they have hyaluronan [6], (pro)coUagen, and fi-bronectin receptors [7]. The first two receptors are nniqnely located on SECs. Elevated levels of serum hyaluronan and fibronectin, that are often fonnd in Uver disease [8], are nsnally the result of dysfunction of the clearance capacity of SECs combined with an increased production by HSCs [9]. 

Proteins and other macromolecules are mainly cleared by high-capacity elimination processes such as renal hltration and liver metabolism. A coadministered drug can affect these processes and lead to serious drug-drug interactions. In addition, drugs that influence receptor-mediated clearance of the therapeutic protein may also result in important drug-drug interactions. 

An increased rate of metabolic clearance has been observed after removal of sialic acid from human, low-density lipoprotein in vivo.472 Sialic acid controls the receptor-mediated uptake of this lipoprotein by fibroblasts. Removal of sialic acid residues accelerates the rate of internalization of the lipoprotein and, subsequently, the regulation of the metabolism of cellular cholesterol.473... 

Production of LDL from VLDL in the plasma With these modifications, the VLDL is converted in the plasma to LDL. An intermediate-sized particle, the intermediate-density lipoprotein (IDL) or VLDL remnant, is observed during this transition. IDLs can also be taken up by cells through receptor-mediated endocytosis that uses apo E as the ligand. [Note Apolipoprotein E is normally present in three isoforms, E2, E3, and E4. Apo E2 binds poorly to receptors, and patients who are homozygotic for apo E2 are deficient in the clearance of chylomicron remants and IDLs. The individuals have familial type III hyperlipoproteinemia (familial dysbetalipoproteinemia, or broad beta disease), with hypercholesterolemia and premature atherosclerosis. Not yet understood is the fact that the E4 isoform confers increased susceptibility to late-onset Alzheimer disease.]... 

The plasma half-life of LDL is about 2 days, and their primary function is the delivery of cholesterol to the tissues. LDL are taken up into cells by two routes, one that is receptor mediated (and is regulated by the cholesterol requirement of the cell) and one that appears to be nonreceptor mediated (and depends entirely on the extravascular concentrations of LDL). The receptor-mediated uptake occurs by binding of apo-BlOO, which is predominantly present on LDL. Hence these receptors are also known as LDL receptors and have been identified on a variety of cell types. In normal humans, about two thirds of total LDL clearance is mediated by the LDL receptor, and about 80-90% of the receptor-mediated uptake occurs in the liver. However, the relative importance of receptor and nonreceptor-mediated LDL uptake can vary depending on factors including diet and different disease states. 

Kuwabara,T.,T. Uchimura, H. Kobayashi, S. Kobayashi, and Y. Sugiyama. 1995. Receptor-mediated clearance of G-CSF derivative nartograstim in bone marrow of rats. Am.J. Physiol. 269 E1-E9. 

The pharmacokinetics of efalizumab are highly influenced by the target expression, indicating the presence of a receptor-mediated clearance pathway [81-83]. Using purified mouse and human T cells, internalization of anti-CDlla antibodies was observed following interaction with CDlla. Internalized antibodies moved in endosomes to lysosomes and were catabolized within the cells [84, 85]. 

P.J. Fielder. 2005. Tissue distribution and receptor-mediated clearance of anti-CDll a antibody in mice. Drug Metab. Dispos. 33 623-629. 

The first adenoviral (Ad)-mediated gene delivery studies for GSDII were performed in GSDII patient fibroblasts, myoblasts, and myotubes (Nicolino et al., 1998 Pauly et al., 1998, 2001). Several important findings came from these early studies including the ability to achieve overexpression of GAA from Ad vectors of up to 19-20-fold over untreated normal cells (Nicolino et al., 1998 Pauly et al., 1998), localization of the Ad-delivered GAA protein to the lysosomes (Pauly et al., 1998, 2001), clearance of accumulated glycogen in treated cells (Nicolino et al., 1998 Pauly et al., 1998), secretion of the 110 kDA precursor form into the culture media (Nicolino et al., 1998 Pauly et al., 1998), and M6P receptor-mediated uptake of GAA secreted from transduced cells by GAA-deficient cells (Nicolino et al., 1998 Pauly et al., 1998). 

Joberg ME, Blom A, Larsson BS, Alston-Smith J, Mats S, Fries E. Plasma clearance of rat bikunin Evidence for receptor-mediated uptake. Biochem J 1995 308 881-887. 

Both IDL and LDL can be removed from the circulation by the liver, which contains receptors for ApoE (IDL) and ApoB-100 (IDL and LDL). After IDL or LDL interacts with these receptors, they are internalized by the process of receptor-mediated endocytosis. Receptors for ApoB-100 are also present in peripheral tissues, so that clearance of LDL occurs one-half by the liver and one-half by other tissues. In the liver or other cells, LDL is degraded to cholesterol esters and its other component parts. Cholesterol esters are hydrolyzed by an acid lipase and may be used for cellular needs, such as the building of plasma membranes or bile salt synthesis, or they may be stored as such. Esterification of intracellular cholesterol by fatty acids is carried out by acyl-CoA-cholesterol acyltransferase (ACAT). Free cholesterol derived from LDL inhibits the biosynthesis of endogenous cholesterol. B-100 receptors are regulated by endogenous cholesterol levels. The higher the latter, the fewer ApoB-100 receptors are on the cell surface, and the less LDL uptake by cells takes place. 

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