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Summary of Nonlinear Pharmacokinetics

Nonlinear pharmacokinetics (in other words, time or dose dependences in pharmacokinetic parameters) can arise from factors related to absorption, first-pass metabolism, binding, excretion and biotransformation. Nonlinearities in absorption and bioavailability can cause increases in drug concentrations that are disproportionately high or low relative to the change in dose. one amongst the more important sources of nonlinearity is that the partial saturation of presystemic metabolism exhibited by such drugs as verapamil, propranolol and hydralazine.

In such cases, circulating drug concentrations are sensitive not only to dose size but also to rate of absorption: slower absorption may decrease the general systemic availability. The binding of medicine to plasma constituents, blood cells and extravascular tissue may exhibit concentration dependence. this could cause pharmacokinetic parameters supported total blood or serum drug concentrations to be concentration-dependent. Often, in these cases, parameters supported free drug concentration appear linear. a crucial consideration in reference to concentration-dependent serum binding is that the difficulty in relating total concentration to a usual therapeutic range if free concentration may be a better indicator of drug effect. Measurement of free concentration is required in these cases, particularly if the intersubject variability in binding is high. An example of this behaviour is antiepileptic drug.