half‐life (t1/2) of a drug, defined as the time taken for half of the administered drug to get eliminated from the body (time taken for drug amount in body to go from A0, to A0/2, or time taken for the drug concentration to be halved), is given by:
Using Equation 1.8, the half‐life of a drug can be calculated from the elimination rate constant kel which is obtained from the semilogarithmic plot of concentration vs. time (Figure 1.2).
Integrating the Equation 1.2 (−dA = CL × C dt) yields
where AUC is the area under the drug concentration‐time profile (Figure 1.2), which may be estimated from the plot by applying the trapezoidal rule. Recognizing that the integral dA over time 0 to t is the dose, Equation 1.9 becomes,
Knowing the dose administered and the AUC, clearance can be calculated using Equation 1.10. The volume of distribution, V, of the drug can be determined using Equation 1.11, knowing that clearance is the product of kel and V.
Most small molecule drugs bind reversibly to plasma proteins such as albumin and alpha‐glycoprotein. Drug binding to plasma proteins is of major interest in pharmacokinetics as it impacts both clearance and volume of distribution. Thus far, the term clearance refers to blood clearance. However, measurements of drug concentrations are often done in plasma, as whole blood contains cellular elements (red and white blood cells, platelets etc.) and proteins (albumin, glycoproteins, globulin, lipoproteins etc.). The clearance of a drug determined using the AUC estimated from plasma drug concentration‐time profile is referred to plasma clearance. To convert plasma clearance to blood clearance, the distribution of a drug between blood and plasma should be measured. The ratio of drug concentrations in blood to plasma is known as blood–plasma ratio (R).
Mean residence time is a parameter closely related to half‐life and is defined as the average time drug molecules spend in the body before being eliminated. It is expressed as the sum of the residence times of all drug molecules, divided by the total number of molecules. If dAe is the number of drug molecules exiting the body at time interval t, MRT is given by:
Differentiating Equation 1.5 (
(1.13)
Recognizing that the rate of decline in A = − rate of amount exiting the body, Ae :
(1.14)
Substituting for dAe using Equation 1.15 in Equation 1.12 and dividing both numerator and denominator by kel, we get
(1.16)
The numerator of equation is the first moment of the concentration–time integral, or the area under the curve formed by time and the product of concentration and time, also called the area under the first moment curve (AUMC). The denominator of equation is the same as AUC as shown below:
(1.17)
Thus, MRT for an IV bolus is given by the ratio of AUMC and AUC
(1.18)
1.2.3 Plasma Protein Binding and Blood–Plasma Ratio
Drugs reversibly bind to plasma proteins depending upon their lipophilicity and ionizability. In general, the greater the lipophilicity of a compound, the greater its extent of plasma protein binding. The binding equilibrium can be represented as:
[P] is protein concentration; Cu and Cb are the unbound and bound concentrations of the drug at equilibrium. The equilibrium constant, KA, also called the affinity constant is given by
(1.19)
n is the number of binding sites per mole of the binding protein. Since the therapeutic concentrations of most drugs are low relative to the total protein concentration, [P] can be assumed to be the total protein concentration [P]Total. The fraction unbound in plasma (fup ) can be obtained from Equation 1.20 in terms of [P]Total or in terms of the concentrations of α1‐acidic glycoprotein (AGP), [P]AGP and albumin [P]albumin:
The fraction unbound in plasma (fup ) thus depends on the concentrations of plasma proteins and the affinity of the drug to the plasma proteins. Albumin is the principal protein to which many drugs bind, followed by AGP. Other plasma proteins include lipoproteins and globulins. The concentrations of various plasma proteins are shown
