PHARMACOKINETIC PARAMETERS of Biopharmaceutics of Orally Ingested Products

This discussion limits its consideration to the movement of orally ingested drugs
through the gastrointestinal tract (GIT). The movement is active rather than passive.
During the sequence from ingestion to elimination, a variety of active processes
common to both foods and drugs play important roles. Several pharmacokinetic
parameters are used to judge the clinical importance of food/drug interactions.
Pharmacy: Basic Concepts demonstrated that the appearance and disappearance of drug concentrations
in whole blood or blood components (principally plasma or serum) are the
primary measures of drug movement into target tissues. Pharmacologic effects occur
when the drug reaches these sites in appropriate amounts. The plasma or serum drug
concentration vs. time profile of a typical, immediate-release tablet is given in Figure
2.1. From this profile, several meaningful parameters can be obtained that relate the
rate and extent of drug absorption from the dosage form. The rate refers to how fast
the drug reaches the systemic circulation, which is generally considered to translate
into the onset and intensity of the intended drug effect. The extent refers to the total
exposure of the drug in the bloodstream. The extent of drug absorption is integral
in determining the duration, termination, intensity, and therapeutic index of the drug.
Drugs may be absorbed by various routes and processes. For most drugs, the
rate of absorption can be classified as a zero-order or first-order rate process.
Although an in-depth discussion of rate orders of reactions is beyond the mission
of this chapter, a general understanding of these rate orders facilitates a deeper
understanding of how food may alter overall rates of drug absorption. The zeroorder
rate process proceeds in a constant fashion and without regard to any other
factor. In terms of drug absorption, a certain amount of the drug will be absorbed
in a given time period and will not change. Usually, zero-order absorption is the

result of specific drug carriers working at their maximal capacity. The first-order
rate process differs considerably from that of a zero-order process. The first-order
rate process will increase as the concentration of drug at the absorption site increases.
In terms of drug absorption, the rate of drug absorption increases as the drug
concentration at the absorption site increases. Figure 2.2 displays the zero- and firstorder
rate processes as a function of drug concentration at the absorption site.
Rate of Absorption (KA)
The overall rate of drug absorption, KA, represents the sum of many individual
rates of processes that eventually lead to the appearance of drug in the bloodstream.
These individual rates include: (1) the rate of disintegration of the dosage form, (2)
the rate of dissolution (or solvation) of the drug from the disintegrated dosage form,
(3) the rate of gastric emptying, (4) the rate of drug degradation in the GIT, and (5)
the rate of intestinal emptying (transit). If food interferes with any of these processes,
then the overall rate of absorption will be affected. Several different methods of
determining the rate of absorption exist, and these methods are covered in detail in
clinical pharmacokinetics textbooks. In this chapter, we will focus on the use of the
KA term, rather than its discovery from experimental data.
As explained previously, one cannot inspect a plasma-drug concentration vs.
time profile and identify the component of the curve that represents KA. KA is
determined, however, by mathematical treatment of the plasma-drug concentration
vs. time data. KA is used to calculate a tangible parameter called the time to maximal
drug concentration (TMAX). This parameter also corresponds to the time to peak
absorption. Figure 2.3 relates TMAX to other clinical pharmacokinetic parameters
important in the assessment of drug absorption. When considering the implications
of the magnitude of KA, one sees that a small TMAX value leads to a rapid onset of
action. Thus, a rapid onset of action correlates to a small TMAX value, which in turn
is proportional to a rapid KA. For certain drugs, food may enhance the rate of
absorption, while the same food may substantially reduce the rate of absorption of
other drugs.

Maximal Drug Concentration (CMAX)
The maximal concentration or peak concentration of drug in plasma after a single
dose occurs at TMAX. Stated differently, CMAX is a function of and is inversely related
to TMAX. CMAX directly impacts the intensity of the pharmacological and/or toxicological
drug action. Therefore, circumstances that may slow the rate of absorption
(and thus increase TMAX) may result in a decrease in CMAX. This in turn may reduce
the intensity of drug action. Figure 2.3 visually demonstrates the relationship
between TMAX and CMAX.
Area under the Plasma Concentration vs. Time Curve (AUC)
AUC is the fundamental pharmacokinetic parameter that denotes the extent of
drug absorption. Many dosing regimens are based on the total systemic exposure of
a drug after a given dose as measured by the plasma-drug AUC. The unusual
dimension of the AUC term (mass × time/volume) is due to the formula used to
derive AUC. Two (x, y) coordinates on the plasma-drug concentration vs. time curve
create a trapezoid, and, as such, the area contained in that trapezoid can be calculated
with elementary geometry. Thus, the “AUC” term is the sum of all the individual
trapezoids formed by the drug plasma concentration vs. time data. The magnitude
of the AUC value influences the intensity, duration and termination of activity (see
Figure 2.1). AUC is also governed by metabolic and elimination pathways; therefore,
the prediction of how food may directly alter the magnitude of AUC is confounding.
One of the main elimination routes of any drug absorbed in the GIT occurs
during its first pass through the liver. As a result of this pathway that is designed to
protect the body from toxins, it is quite likely that not all of the drug that is absorbed
will reach the systemic circulation. The AUC value is thus used to calculate the
bioavailability (F) of the drug or the percentage of the dose that reaches the systemic
circulation. The following expressions describe the relationships among the parameters
discussed in this section.
AUC ∝ F
TMAX ∝ 1/KA
CMAX ∝ KA
CMAX ∝ F