Pharmacokinetic Terminology

Understanding of the literature in the field of pharmacol­ogy requires familiarity with a number of special concepts and terms. These are defined in textbooks (Baggot 1977; Riviere 1999) and review articles (Riviere 1988a, b; Martinez 1998a, b, c, d, e; Toutain et al.

Pharmacokinetics is the mathematical description of concentration changes of drugs within the body with time. The drugs are described as distributing into and out of compartments, which are mathematical but not physio­logic entities. The drug distributes instantaneously and homogeneously into the central compartment when given intravenously. The central compartment is often equivalent to blood plasma and extracellular fluid of highly perfused organs. The peripheral compartment, into and out of which drugs may transfer more slowly, represents less well- perfused tissues such as muscle, skin, and fat. Rate con­stants describe drug transfer between compartments and out of the body.

The volume of distribution (V_d) describes the relation­ship between the amount of drug in the body and its plasma concentration:

V (mLl Total drug in the body(mg)

^d Concentration of the drug in plasma (mg / mQ

Goat Medicine, Third Edition. Mary C. Smith and David M. Sherman. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.

If the body appears to behave as a single homogeneous distribution compartment, drug disposition is described by a one-compartment open model. This model assumes that changes in tissue drug concentrations are reflected quanti­tatively by changes in plasma concentration. However, the drug concentrations are not necessarily the same in all body tissues at one time. The term “open,” when applied to a model, means that drug leaves the system.

The disposition of many drugs can be defined by a two- compartment open model, as depicted by the central and peripheral compartments, with elimination occurring only from the central compartment. With some drugs a three- compartment open model is needed, because the plasma drug concentration over time can be best described by a triexponential curve.

The apparent volume of the central and peripheral com­partments for each drug depends on blood flow, the drug's ability to enter the tissues from the circulation, and the extent of tissue binding. Increasing body water volume increases V_d, while dehydration or increasing the fraction of bound drug in the blood decreases V_d. Drug binding in tissues can cause the apparent volume of distribution to exceed the real volume. Neonates have higher percent total body water than adults (Martinez 1998b). The volume of distribution tends to decrease with age.

In a two-compartment model, drugs are assumed to enter the system only via the central compartment and to leave it, by biotransformation and elimination, only from the central compartment. The rate of drug removal from a compart­ment is considered to be proportional to the concentration of drug in that compartment. During the initial or distribution phase, distribution to the peripheral compartment occurs simultaneously with elimination from the body. During the distribution phase, there is a rapid decline in plasma concen­tration, described by an alpha rate constant or distribution half-life. After distribution is complete, elimination predom­inates, and the change in drug concentration is described by a beta rate constant or elimination half-life. In some drugs with extensive tissue binding, elimination slows later on during a gamma phase that is controlled by the rate of release of drug from its binding sites.

Total body clearance is a parameter that estimates drug elimination from the body by all routes relative to the con­centration of drug in serum:

Cl rate of elimination serum drug concentration

It is expressed in terms of volume per unit time and rep­resents the volume of serum completely cleared of the drug by all elimination processes per unit time.

The elimination half-life is the time required for the total amount of drug in the body to decrease by half. The half­life in the body is directly related to the volume of distribu­tion and inversely related to the clearance of the drug from the body by metabolism and/or excretion:

-0.693 ? Vd

^T1/2 ~~

Cl

Although 97% of the drug is eliminated from the body in five half-lives, the half-life derived during pharmacokinetic studies depends on both the clearance and the volume of distribution, and thus is altered by disease states.

The systemic availability, often expressed as a percent, is a measure of the extent of absorption of a drug given by something other than the intravenous (IV) route. For instance, the plasma concentration-time curve is plotted after oral (PO) and after intravenous (IV) administration. The area under the curve (AUC), expressed for instance as ug-h/mL, is calculated for the two curves and the ratio (AUC)PO : (AUC)IV gives the extent of absorption. Bioavailability also depends on the rate of absorption, which affects the peak plasma concentration achieved and the time to that peak. Absorption continues after the peak, but even if the drug has a high systemic availability, slow absorption may cause subtherapeutic plasma levels.