As the concentration of drug increases, the unbound fraction eventually also must increase (as all binding sites become saturated when drug concentrations in plasma are in the range of 10s to 100s of mg/mL). For a drug that is metabolized by the liver with a low intrinsic clearance-extraction ratio, saturation of plasma-protein binding will cause both V and CL to increase; t1/2 thus may remain constant (Equation 1-9). For such a drug, Css will not increase linearly as the rate of drug administration is increased. For drugs that are cleared with high intrinsic clearance-extraction ratios, Css can remain linearly proportional to the rate of drug administration. In this case, hepatic clearance will not change, and the increase in V will increase the t1/2 by reducing the fraction of the total drug in the body that is delivered to the liver per unit of time. Most drugs fall between these two extremes.
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