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Clearance is the sum of all drug‐eliminating processes, principally determined by hepatic metabolism and renal excretion. It can be defined as the theoretical volume of fluid from which a drug is completely removed in a given period of time.

When a drug is administered continuously by intravenous infusion or repetitively by mouth, a balance is eventually achieved between its input (dosing rate) and its output (the amount eliminated over a given period of time). This balance gives rise to a constant amount of drug in the body which depends on the dosing rate and clearance. This amount is reflected in the plasma or serum as a steady‐state concentration (Css). A constant rate intravenous infusion will yield a constant Css, while a drug administered orally at regular intervals will result in fluctuation between peak and trough concentrations (Figure 1.3).

Figure 1.3 Steady‐state concentration–time profile for an oral dose (—) and a constant rate intravenous infusion (‐ ‐ ‐ ‐ ‐).

Clearance depends critically on the efficiency with which the liver and/or kidneys can eliminate a drug; it will vary in disease states that affect these organs, or that affect the blood flow to these organs. In stable clinical conditions, clearance remains constant and is directly proportional to dose rate. The important implication is that if the dose rate is doubled, the Css_average doubles: if the dose rate is halved, the Css_average is halved for most drugs. In pharmacokinetic terms, this is referred to as a first‐order or linear process, and results from the fact that the rate of elimination is proportional to the amount of drug present in the body.