Catabolism, and clearance

In terms of pharmacokinetics, many host factors, such as the route of administration, the metabolism, the catabolism and clearance will considerably determine the anti neoplastic success of a drug. One major difficulty with the clinical effectiveness of chemotherapy of neoplastic diseases is the requirement that it kill malignant tumor cells at doses that allow cells in the patient s vital organs to survive so that the recovery can occur. In other words, it is to obtain a reasonably safe therapeutic index favoring introduction into clinical practice. 

Measuring both protein and gene expression is important, because evidence is accumulating that the two levels are often not closely correlated. Many other factors besides transcription of the gene are important. These factors include splicing, translation, posttranslational modifications, binding, catabolism, and clearance. Some protein biomarkers will be related to drug action. 

Traditionally, the duration of a toxicity study depends on the intended clinical use and disease duration. The potential immunogenicity of the human protein is a significant issue since antibody binding can partially or completely inhibit the biological activity of that protein, affect its catabolism or alter its distribution and clearance. Any multiple-dose study therefore should include evaluation of the impact of antibody formation, including their neutralizing capacity. However, antibody formation in itself should not be a reason for termination of a toxicity study, particularly if the antibodies are not neutralizing or do not alter the pharmacodynamics of the protein. 

In isolated hepatocytes, after maximum induction of tryptophan dioxygenase by glucocorticoids, the uptake of tryptophan into the cells has a control coefficient of 0.75, whereas the control coefficient of tryptophan dioxygenase falls to 0.25. Therefore, the induction of tryptophan dioxygenase has only a limited effect on tryptophan catabolism and NAD synthesis (Salter and Pogson, 1985 Salter et al., 1986). In isolated perfused liver, although cortisol leads to a several-fold increase in tryptophan dioxygenase activity, there is only a relatively small increase in the rate of clearance of tryptophan from the perfusion medium (Kim and Miller, 1969). 

LDL, the major cholesterol transport lipoprotein, having virtually only apolipoprotein B-lOO, is mostly derived from VLDL catabolism and cellular synthesis. When fasting and when normal subjects are on low-fat intake, most cholesterol is synthesized and used in the extrahepatic organs, whereas most of the cholesterol carried by LDL is taken up by the liver for catabolism. In patients with homozygous familial hypercholesterolemia, enhanced synthesis of LDL may occur because LDL clearance is reduced as a consequence... 

Pseudo-renal failure occurs when either the blood urea nitrogen (BUN) or creatinine concentration rises suggesting a decrease in renal function, despite maintenance of the GFR. The BUN concentration commonly increases without an increase in creatinine concentration during corticosteroid or tetracycline therapy. These drugs cause protein catabolism and thereby increase ureagenesis and the BUN concentration as the result of tissue breakdown. The GFR is unchanged and accurately reflected by the creatinine clearance and creatinine concentration. 

The experimental data of plasma and urine radioactivities were analyzed by the non-compartmental approach (Rescigno and Gurpide, 1973), as described in details previously (Bianchi et al., 1979). The formulas utilized in this approach allow to determine the following parameters of uric acid kinetics total metabolic clearance rate (MCR), mean residence time of the tracer, total distribution volume (TDV, plasma equivalent), fractional catabolic rate (FCR, relative to TDV), and clearance rate of C-uric acid via the renal route (MCR] ). The total turnover rate (TR) and the total pool of exchangeable uric acid are then obtained as the product of, respectively MCR or TDV by the plasma urate concentration. The extrarenal disposal of uric acid (bacterial uricolysis in the gut, skin desquamation) is determined as the difference between the total metabolic clearance rate and the clearance rate of uric acid through the kidney route. 

The clearance of labeled chylomicrons from the blood is rapid, the half-time of disappearance being under 1 hour in humans. Larger particles are catabolized more quickly than smaller ones. Fatty acids originating from chylomicron triacylglycerol are delivered mainly to adipose tissue, heart, and muscle (80%), while about 20% goes to the liver. However, the liver does not metabolize native chylomicrons or VLDL significantly thus, the fatty acids in the liver must be secondary to their metabolism in extrahepatic tissues. 

In humans the clearance rate of Hb is higher than that of HpHb (L4, Lll). Murray et al. (M6) found this also to hold for rabbits and, by studying the elimination in nephrectomized animals, they also proved that the difference was not due to urinary loss of Hb. Analysis of the organs proved that the HpHb complex and Hb were assimilated mainly in the liver and were catabolized with an early reappearance of the iron as transferrin iron within 30 minutes. The free Hb accumulated also in the tubular cells of the kidneys. No data have been published suggesting that the spleen is of any appreciable importance in this respect. No typical exponential clearance of the HpHb complex from plasma was observed (L10, Lll) in the first few experiments. Lathem and Worley (L4) found that HpHb disappeared at a simple exponential rate in 5... 

The unlabeled metabolite, drug, or other substance under study in a kinetic analysis of its biosynthesis/entry (appearance) and catabolism/clearance (disappearance). 

As the lipoproteins are depleted of triacylglycerol, the particles become smaller. Some of the surface molecules (apoproteins, phospholipids) are transferred to HDL. In the rat, remnants that result from chylomicron catabolism are removed by the liver. The uptake of remnant VLDL also occurs, but much of the triacylglycerol is further degraded by lipoprotein lipase to give the intermediate-density lipoprotein (IDL). This particle is converted into LDL via the action of lipoprotein lipase and enriched in cholesteryl ester via transfer from HDL by the cholesteryl ester transfer protein. The half-life for clearance of chylomicrons from plasma of humans is 4-5 min. Patients with the inherited disease, lipoprotein lipase deficiency, clear chylomicrons from the plasma very slowly. When on a normal diet, the blood from these patients looks like tomato soup. A very-low-fat diet greatly relieves this problem. 

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]. 

Newborn babies have a low plasma LDL cholesterol, between 25 and 50 mg/100 ml (K36), a level similar to that found in many animal species (C2, M35). Goldstein and Brown have hypothesized that the marked rise which occurs in industrialized man, with LDL-cholesterol levels of over 100 mg/100 ml, may be attributed to suppression of LDL receptors as a result of environmental factors (B55, G19). They adduce evidence from studies on LDL turnover performed by Bilheimer and others that indicates that dogs, baboons, and humans each produce about 15 mg LDL cholesterol per kilogram body weight per day, but the very marked differences in plasma LDL-cholesterol levels in these species is the result of a fractional catabolic rate lower in the baboon than in the dog and much lower in man (G19). Miller also summarizes evidence from others suggesting that the slow rise in plasma LDL concentration seen with age in men and women is associated with a corresponding fall in the fractional catabolic rate of LDL, and he hypothesizes that the decrease in efficiency of LDL clearance with advancing age is a consequence of a decrease in either the number or the function of LDL (B-100,E) receptors (M33). 

Effect of IgG Structure on Plasma IgG Clearance and Tissue Catabolism... 

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