Clearance is the most important concept to consider when designing a rational regimen for long-term drug administration. The clinician usually wants to maintain steady-state concentrations of a drug within a therapeutic window associated with therapeutic efficacy and a minimum of toxicity for a given agent. Assuming complete bioavailability, the steady-state concentration of drug in the body will be achieved when the rate of drug elimination equals the rate of drug administration. Thus:

where CL is clearance of drug from the systemic circulation and Css is the steady-state concentration of drug.

Metabolizing enzymes and transporters (see Chapters 2 and 3) usually are not saturated, and thus the absolute rate of elimination of the drug is essentially a linear function (first-order) of its concentration in plasma, where a constant fraction of drug in the body is eliminated per unit of time. If mechanisms for elimination of a given drug become saturated, the kinetics approach zero order, in which a constant amount of drug is eliminated per unit of time. Clearance of a drug is its rate of elimination by all routes normalized to the concentration of drug in some biological fluid where measurement can be made:

Thus, when clearance is constant, the rate of drug elimination is directly proportional to drug concentration. Clearance is the volume of biological fluid such as blood or plasma from which drug would have to be completely removed to account for the clearance (e.g., ml/min/kg). Clearance can be defined further as blood clearance (CLb), plasma clearance (CLp), depending on the measurement made (Cb, Cp).

Clearance of drug by several organs is additive. Elimination of drug may occur as a result of processes that occur in the GI tract, kidney, liver, and other organs. Division of the rate of elimination by each organ by a concentration of drug (e.g., plasma concentration) will yield the respective clearance by that organ. Added together, these separate clearances will equal systemic clearance:

renal hepatic other - '

Systemic clearance may be determined at steady state by using Equation (1—2). For a single dose of a drug with complete bioavailability and first-order kinetics of elimination, systemic clearance may be determined from mass balance and the integration of Equation (1—3) over time:

where AUC is the total area under the curve that describes the measured concentration of drug in the systemic circulation as a function of time (from zero to infinity) as in Figure 1—5.

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Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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