Clearance of macromolecules

The mixed function oxidases and cytochrome P450 enzyme systems do not play a role in the clearance of macromolecules. Nor do large proteins interact with transporter proteins such as P-gp, despite the fact that one site of clearance is the... 

Defective lymphatic clearance of macromolecules and lipids from interstitial tissue (prolonged retention of these substances)... 

Enantioselective differences in absorption, metaboHsm, clearance, dmg— macromolecule binding affinity, and other factors, which culminate in the observed enantioselective efficacy of chiral dmgs, are considered herein. More inclusive Hsts of optically active dmgs and theit enantioselective differences are available (93). 

On the basis of the above data it has been hypothesized that the conductivity of PFCM is due not to the contact between the filler particles but the current passes across the thin (less than 1 -2 microns) polymer interlayers. The conductivity arises when a spontaneous pressure exceeding the threshold value develops in the material. The overstresses apparently arise as a result of PP crystallization in the very narrow gaps between the filler particles [312], Since crystallization must strongly affect the macromolecular conformation whereas the narrowness of the gap and fixed position of molecules on the filler prevent it, the heat released in the process of crystallization must, in part, be spent to overcome this hindrance, whereby a local high pressure may arise in the gap. This effect is possible only where there are gaps of the size comparable with that of macromolecules. The small gap thickness will also hamper pressure relaxation, since the rate of flow from such a narrow clearance should be negligibly small. 

Factors known to influence the clearance of drugs from interstitial sites, following extravasation or parenteral interstitial or transepithelial administration, include size and surface characteristics of particles, formulation medium, the composition and pH of the interstitial fluid, and disease within the interstitium. Studies indicate that soluble macromolecules smaller than 30 nm can enter the lymphatic system, whereas particulate materials larger than 50 nm are retained in the interstitial sites and serve as a sustained-release depot. The use of lipids or an oil in a formulation and the presence of a negative surface charge all appear to... 

Fig. 17. Comparison of blood clearance of glycoproteins and asialoglycoproteins. Removal of terminal sialic acid moieties by enzyme (neuraminidase) exposes the penultimate galactose moieties. The modified macromolecules are removed from the bloodstream very fast due to their biorecognition by the asialoglycoprotein receptor on hepatocytes. Based on data from [250]...

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. 

Noguchi Y, Wu J, Duncan R et al (1998) Early phase tumor accumulation of macromolecules a great difference in clearance rate between tumor and normal tissues. Jpn J Cancer... 

Since UFR cannot exceed blood flow through the hemofilter/ that establishes the theoretical upper limit for CLuf- The major determinants of SC are molecular size and the unbound fraction of a compound in plasma water. Values of SC may range from 0/ for macromolecules that do not pass through the pores of the hemofilter membrane/ to 1, for small-molecule drugs that are not protein bound. Although less information has been accumulated about the ultrafiltration clearance of drugs than about their dialysis clearance/ in many cases the unbound fraction of drug in plasma water can be used to approximate SC. 

In Table 32.6 the predicted parameter estimates derived from the allometric equations in Table 32.5 are compared with the corresponding parameter estimates reported in humans. The observed values of Pi for the macromolecules listed fall within the expected range of observed results. However the observed clearances of Factor IX (FIX) and interleukin-12 (IL-12) were not predicted from allometry. Factors such as species specificity in the endothelial binding of FIX (22) or saturation of clearance mechanisms may account for the inability to predict these parameters in humans. 

Finally, clearance may change over time for macromolecules whose clearance is mediated by cell surface receptors and, in the case of mABs, antigens. This is illustrated by an experiment in three patients with metastatic breast cancer who received G-CSF for two consecutive days as a continuous infusion (45). Absolute neutrophil counts were obtained every morning and there was a very strong positive correlation between neutrophil count and G-CSF clearance (Figure 32.12). Clearance on day 2 was 4.6 mL/hr/kg, increasing to 8.3 mL/hr/kg on day 9. Thus, neutrophil production may mediate the clearance of G-CSF. 

FIGURE 47-2. Movementof various macromolecules across the glomerular capillary. The fractional clearance of each macromolecule decreases as molecularweight(MW) increases. The disproportionately greater restriction of albumin movement indicates importance of factors other than size, such as negative charge of albumin. (Adapted from HuttMP, Kelleher SR Proteinuria and the nephrotic syndrome. In Schrier RW, ed. Renal and Electrolyte Disorders, 3rd ed. Boston, Little, Brown, 1986 p. 568.)... 

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