Clearance is the volume of blood or plasma from which a drug would have to be completely removed to account for the fall in concentration.

Cl = Rate of elimination/Concentration

Thus, the clearance of a drug is used to describe the rate of removal by either excretion or metabolism. This is the total body clearance. Clearance may also be divided according to organs of elimination (e.g. renal clearance and hepatic clearance; in which case it is the amount of blood or plasma from which drug has been removed by that organ).

It is probably the most difficult pharmacokinetic term to understand. Related closely to Vd it is expressed as a volume/time (e.g. mL/min or L/hr). It is also not directly measured but calculated from the concentration and the rate with which the concentration falls. Because the rate of elimination of most drugs is proportional to the concentration, clearance is generally a constant value for most individuals. In contrast to the Vd, it is easy to visualise how clearance may be altered.

The clearance of a particular organ is a function of the blood flow through that organ and the proportion of the drug that is removed (the extraction ratio).

e.g. Cl (renal) = Renal Blood flow * Extraction ratio

Thus the renal clearance of most drugs will be reduced if renal blood flow is reduced (e.g. in shock). Clearance of certain therapeutic interventions can be directly measured. Later we will explore an example of dialysis in carbamazepine poisoning

6.10 HALF LIFE (AKA: ELIMINATION HALF-LIFE)

The half life (t ½) is the time taken for the concentration of the drug to fall to half its original value. For most drugs, this is constant across a wide range of concentrations. For example, this means the same time is taken halve the concentration when the total amount is 10 grams as when the total amount is 10 milligrams. (This is first order kinetics.)

First order and saturated kinetics

For most drugs used in therapeutic doses the body does not have to use all its capacity to metabolise or eliminate the drug. Instead, a fixed proportion of what ever concentration is presented to the metabolic process is removed. In this situation the concentration declines
exponentially with time. (Figure 1). This is termed 1st order kinetics.

This is not the case for a few therapeutic drugs (phenytoin and alcohol) where all the enzyme capacity is being used (saturated). In this situation a fixed amount of drug is removed and the concentration falls in a linear fashion. (Zero order kinetics)

In first order kinetics the fall in blood concentrations is described with the exponential equation:

Cpt =Cp0 * e-kt

Where:

Cpt is the concentration at time t

Cp0 is the concentration at time zero

k is the elimination rate constant

This equation can be manipulated to form other equations that describe various kinetic parameters. The most convenient manipulation is to transform it into a linear expression by using the natural logarithm (log to base 2) of each side.

lnCpt =lnCp0 - kt

This produces a straight line when concentrations are graphed with on a logarithmic y-axis.

Link to Problems for Discussion

## Table of Contents

## Clearance (CL)

Clearance is the volume of blood or plasma from which a drug would have to be completely removed to account for the fall in concentration.

Cl = Rate of elimination/ConcentrationThus, the clearance of a drug is used to describe the rate of removal by either excretion or metabolism. This is the total body clearance. Clearance may also be divided according to organs of elimination (e.g. renal clearance and hepatic clearance; in which case it is the amount of blood or plasma from which drug has been removed by that organ).

Total clearance = Cl (renal) + Cl (liver) + Cl (lung), etcIt is probably the most difficult pharmacokinetic term to understand. Related closely to Vd it is expressed as a volume/time (e.g. mL/min or L/hr). It is also not directly measured but calculated from the concentration and the rate with which the concentration falls. Because the rate of elimination of most drugs is proportional to the concentration, clearance is generally a constant value for most individuals. In contrast to the Vd, it is easy to visualise how clearance may be altered.

The clearance of a particular organ is a function of the blood flow through that organ and the proportion of the drug that is removed (the extraction ratio).

e.g.

Cl (renal) = Renal Blood flow * Extraction ratioThus the renal clearance of most drugs will be reduced if renal blood flow is reduced (e.g. in shock). Clearance of certain therapeutic interventions can be directly measured. Later we will explore an example of dialysis in carbamazepine poisoning

## 6.10 HALF LIFE (AKA: ELIMINATION HALF-LIFE)

The half life (t ½) is the time taken for the concentration of the drug to fall to half its original value. For most drugs, this is constant across a wide range of concentrations. For example, this means the same time is taken halve the concentration when the total amount is 10 grams as when the total amount is 10 milligrams. (This is first order kinetics.)

For most drugs used in therapeutic doses the body does not have to use all its capacity to metabolise or eliminate the drug. Instead, aFirst order and saturated kineticsfixed proportionof what ever concentration is presented to the metabolic process is removed. In this situation the concentration declinesexponentially with time. (Figure 1). This is termed

1st order kinetics.This is not the case for a few therapeutic drugs (phenytoin and alcohol) where all the enzyme capacity is being used (

saturated). In this situation afixed amountof drug is removed and the concentration falls in a linear fashion. (Zero order kinetics)In first order kinetics the fall in blood concentrations is described with the exponential equation:

Cpt =Cp0 * e-ktWhere:

This equation can be manipulated to form other equations that describe various kinetic parameters. The most convenient manipulation is to transform it into a linear expression by using the natural logarithm (log to base 2) of each side.

lnCpt =lnCp0 - ktThis produces a straight line when concentrations are graphed with on a logarithmic y-axis.

See also