Description
Pharmacokinetics is the mathematical characterization of the time course of drug absorption (A), distribution (D), metabolism (M), and excretion (E) [ 1 ]. Taken together, ADME processes relate to the intensity and time course (onset, duration, etc.) of drug action, as such their understanding is important to guiding rational drug therapy. Over the past 50 years, scientifi c advances have revolutionized drug devel-opment and design and clinical decision making. These include improvements in quantitating drug and metabolite concentrations in biologic matrices (plasma and tissue), measuring drug effects, and understanding how genetics, metabolic path-ways, and drug transporters infl uences drug disposition. This chapter will provide an overview of how ADME and its applications may be used clinically to enhance the efficacy and minimize the toxicity of centrally acting pharmacologic agents.
A major challenge for health-care professionals in clinical psychopharmacology is in understanding and adjusting for individual differences in a drug’s response. Knowledge of a drug’s pharmacokinetic characteristics can be leveraged to help resolve these issues and formulate rational drug therapy decisions. As an example, understanding the absorption and distribution characteristics of a drug allows one to predict the amount of an administered dose that is expected to enter the bloodstream and reach its site of action. Further, an understanding of drug metabolism and elimi-nation allows for the prediction of drug concentrations when it is administered on a repeated basis (i.e., under steady-state conditions); this allows for the rational selec-tion of dosing regimens. Dose and regimen selection must also take drug interac-tions, genetic polymorphisms, comorbid conditions, and aging into account since all of these can impact drug exposure, effi cacy, and toxicity [ 2 ].
From a pharmacokinetic perspective, the body is often characterized as a series of compartments that are reversibly interconnected through a central compartment. Compartments are purely mathematical locales and do not necessarily represent a specifi c physiologic or anatomic area, but are fashioned when organs and tissues which display similar pharmacokinetic characteristics for a given drug are grouped together. Because of these similarities, it is assumed that a drug within each com-partment is distributed homogenously, and drug movement in and out of each com-partment displays consistent kinetics. By establishing these compartments, mathematical models can be created to characterize the separate aspects of ADME to describe variations in each and help predict drug actions.
Drugs that behave mathematically in the body as though they reside within a single homogenous space are described using a one-compartment model. These drugs are treated as though there is one central compartment into which they are absorbed, rapidly distributed, and eliminated. In reality, the body is not a single homogenous compartment and actual tissue concentrations will vary considerably throughout. However, in using this model, it is assumed that there is kinetic homo-geneity throughout the body, and thus the rate of change of drug concentrations in one tissue will refl ect a corresponding change in drug concentrations in all other tissues [ 3 ]. Typically plasma or serum drug concentration data are used as the pri-mary reference for this compartment. Consequently, a 10 % increase in plasma drug concentrations would be refl ected by a 10 % increase in tissue drug concentrations over the same time frame. For one-compartment psychopharmacologically active agents, this relative increase in tissue concentrations would include the central ner-vous system (CNS), which represents the site(s) of drug action.
Unfortunately, not all drugs fi t well into a one-compartment model and this includes many psychopharmacologic agents. For such drugs, their tissue distribu-tion is not necessarily rapid or uniform throughout the body; consequently, rates of change in tissue drug concentrations do not consistently match those of the central compartment. These drugs are typically described mathematically as having multi-ple (two or more) compartments. Such a situation can easily be observed when suf-fi cient plasma concentrations are plotted over time following an intravenous bolus injection of a drug. Upon injection, plasma concentrations will initially be high because all of the drug is located in the blood. This is quickly followed by a period of rapid decline in plasma concentrations, due primarily to drug distribution out of the central compartment and into the tissues. This period is called the distributive phase, although some drug elimination (e.g., metabolism by the liver and/or excre-tion by the kidney) also occurs simultaneously. For drugs with three or more com-partments, multiple distributive phases, each with distinct rates of decline may exist. As each distributive phase may last from minutes to hours, they can only be prop-erly delineated with multiple plasma concentrations obtained during each phase; a process that is not typically feasible in the clinical setting. Finally as drug distribu-tion reaches its peak, a pseudo-equilibrium is established between the individual tissues and the central compartment. The continued decline in plasma concentra-tions will now slow, and the subsequent changes in plasma concentrations will now largely represent drug metabolism and/or excretion. This phase is called the elimi-nation phase ; it is during this time that a drug’s elimination half-life ( T 1/2 ) can be calculated, and it is anticipated that subsequent changes in plasma concentrations accurately refl ect changes in tissue concentrations throughout the body, similar to that of a one-compartment model.