Saturation, of plasma protein binding

Elimination of phosphorothioated AS-ODN takes place primarily via the urine. Approximately 30% of the injected dose is found in the urine within 24 h [110,113], Althought in most cases only metabolites of AS-ODN could be demonstrated in the urine [110,118], Agrawal and co-workers described the excretion of intact AS-ODN in the urine after a dose of 30 mg kg [126], The saturation of plasma protein binding and proximal tubular uptake could explain this observation [114,116],... 

Once a toxic compound has been absorbed, the disposition of it in vivo may also be affected by the dose. Thus, saturation of plasma-protein binding sites may lead to a significant rise in the plasma concentration of free compound, with possible toxic effects. This, of course,... 

Saturation of plasma protein binding For example, disopyramide shows increase in volume of distribution with increased dose. 

As observed with other drugs, ormetoprim exhibited a low percentage of plasma protein binding in fish. For trout, this averaged 31%. This binding was nonspecific and non-saturable. Plasma protein binding of ormetoprim also has been described as non-specific in other species such as sculpin, skate, shark and flounder (53). 

Heparin is metabolized according to a saturable pathway. Thus, half-life varies with dose. The half-life within the low therapeutic dose range is approximately 30 minutes. This may increase to as much as 3 hours, with doses in the high therapeutic range. These values may increase in individual patients, in proportion to the degree of plasma protein binding. 

Phenylbutazone is metabolized by the liver at a rate of about 15-25% per day (B33), but plasma levels do not increase proportionately with increasing doses of the drug. The work of Burns et al. (B33) indicates that above a certain level plasma phenylbutazone concentrations plateau. The concentration at which this occurs varies among individuals and is probably a reflection of the level at which saturation of high-affinity plasma protein binding sites occurs. 

This is known as Michaelis-Menten or saturation kinetics. The processes that involve specific interactions between chemicals and proteins such as plasma protein binding, active excretion from the kidney or liver via transporters, and metabolism catalyzed by enzymes can be saturated. This is because there are a specific number of binding sites that can be fully occupied at higher doses. In some cases, cofactors are required, and their concentration may be limiting (see chap. 7 for salicylate, paracetamol toxicity). These all lead to an increase in the free concentration of the chemical. Some drugs, such as phenytoin, exhibit saturation of metabolism and therefore nonlinear kinetics at therapeutic doses. Alcohol metabolism is also saturated at even normal levels of intake. Under these circumstances, the rate of... 

Subcutaneous administration leads to a peak heparin level 2 h after injection and an onset of anticoagulant effect within 1-2 h. Intravenous administration leads to an immediate peak heparin level with anticoagulant activity within 20-30 min. Heparin binds extensively to a number of plasma proteins. Its volume of distribution is 0.07lkg in adults. The pharmacokinetics of heparin is complex and incompletely understood. Heparin metabolism occurs primarily in the reticuloendothelial system by desulfation. The LMWH agents have longer half-lives than standard heparin. Heparin s elimination half-life increases disproportionately with increasing dose, indicating saturable kinetics. 

Non-linearity may arise at at any one of the various pharmacokinetic steps, such as absorption, distribution and/or elimination. For example, the extent of absorption of amoxicillin decreases with an increase in dose. For distribution, plasma protein binding of disop5Tramide is saturable at the therapeutic concentration, resulting in an increase in the volume of distribution... 

During a drug s development it is important to investigate the effect on exposure of changing the dose, and to prove that clearance is dose-independent. When Clp, V2, and tyx remain constant over a dose range and over time, a drug can be said to have linear PK. If an elimination process becomes saturated, AUC tends to increase with dose more than one would expect, if absorption or plasma protein binding are saturated, AUC tends not to increase with dose as much as one would predict. 

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