Drug Kinetics

By P. G. WELLING

1 Introduction

The continuing search for new and improved drugs, and the consequent introduction into clinical practice of increasingly potent therapeutic agents, re-emphasizes the need for a greater quantitative understanding of the processes of drug absorption, distribution, metabolism, and excretion and the rates at which these events occur.

This chapter is presented in a similar form to its predecessors in Volumes 2 and 3, and attempts to describe major observations, conclusions, and accomplishments from studies on drug kinetics during the review period. The literature coverage is not as exhaustive as in Volume 3. However, the writer has attempted to include sufficient material for the reader to appreciate the most recent trends in this area of research.

The maturity of the study of drug kinetics may be reflected in the recent publishing of textbooks on pharmacokinetics, fundamentals of clinical pharmacokinetics, biopharmaceutics and pharmacokinetics. Other useful texts include monographs on biopharmaceutics and drug interactions, and pharmacokinetics, drug metabolism, and drug interaction.

Increasing acceptance of the importance of a knowledge of drug kinetics in therapy is also indicated by the contents of various symposia on clinical pharmacokinetics, pharmacology and pharmacokinetics, individualization of drug therapy, and pharmacokinetics and drug effects. Several reviews have been published relating to clinical aspects of pharmacokinetics, drug level-response relationships, the use of computers in drug therapy, and the influence of environmental and body temperature and age on drug pharmacodynamics and pharmacokinetics.

During the review period, theoretical and practical approaches to the kinetics associated with drug interactions have been described, and further evidence has been presented of the importance of non-linear pharmacokinetics in the correct analysis of some in vivo data, particularly in cases of saturable processes. Theoretical papers have appeared concerning polygenic factors in drug kinetics, the use of eigenvector decomposition in multicompartment modeling, kinetic treatment of non-uniform and variable dosage regimens, data treatment in mammillary models of n compartments with different routes of administration, and also the use of hydrodynamic diffusion analogue models in the solution of pharmacokinetic problems.

Dedrick has discussed problems associated with relating animal data to man in terms of physical and chemical factors. Some aspects of the present status of bioavailability and tissue distribution studies habe been reviewed by Garrett, while Wagner has reviewed the evidence of non-linear phenomena in drug kinetics and has presented guidelines for correct analysis of drug disposition in this light. As in all physical and chemical phenomena, a limiting factor in distinguishing linear and non-linear processes is the noise level in, and reproducibility of, collected data. These problems will continue to give rise to interpretation inconsistencies with studies conducted in biological systems in vivo. Words of warning have been sounded regarding the statistical validity of some types of computer fitting and also methodology and design of pharmacokinetic studies.

Drug Absorption. — The importance of the route of administration in drug absorption and disposition has been reviewed by Gibaldi and Perrier and by Riegelman and Rowland. The latter authors emphasize the importance of the 'first-pass' effect for p.o. dosed drugs and showed that the hepatic extraction of a drug during absorption is controlled by Michaelis–Menten-type kinetics and also the concentration of drug exposed to the liver per unit time. Other authors have described the influence of gastric emptying, various physiological factors, and also antacids on gastro-intestinal drug absorption rates.

In vitro and in situ studies in rats have provided further evidence of the importance of solvent drag on intestinal drug absorption and the negative influence of K+ on drug absorption due to water uptake by epithelial cell mernbranes.

Nayak and Benet have described an elegant series of experiments designed to study the gastro-intestinal absorption of drugs in the rhesus monkey. By means of suitably implanted Foley catheters, drug absorption from the stomach and intestine can be determined from either liquid or solid dosage forms. Examples of the preparations for stomach and intestinal absorption studies are reproduced in Figure 1.

Although some difficulties were encountered in the maintenance of these preparations over prolonged periods, they provide an excellent basis for drug absorption studies from specific sites in the gastro-intestinal tract.

The Loo–Riegelman method for calculating drug absorption rates has been criticized by Boxenbaum and Kaplan, who showed that substitution of a two-term Taylor expansion to simplify absorption terms may lead to serious calculation errors. Various other aspects of the Loo–Riegelman absorption method in compartment model systems have been presented by Wagner, who also discussed the application of the Wagner–Nelson absorption method to both one- and two-compartment model data in the presence and absence of competing reactions at absorption sites. A further method for calculating the rate and extent of drug absorption has been described, which is based on the integration of the model-independent Kwan–Till method and either of the previously cited model-dependent methods. This procedure utilizes both plasma and urine data and incorporates one or more internal checks, which facilitate more accurate interpretation of absorption and distribution processes.

As an alternative to these rather complex methods, a more simple model-independent procedure has been proposed for calculating drug absorption rates. In this method, the general solution for the absorption rate constant, ka, is given by equation (1), where Mn is the slope of the terminal regression of the logarithm of

[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (1)

either the plasma concentration or urinary drug-excretion curves, intercept (i.v.) and intercept (l°) are the antilogarithms of the respective ordinate intercepts after i.v. and first-order input, and D2 and D1 are the i.v. and first-order drug doses respectively. The relative simplicity of this method makes it attractive, but it does require i.v. data and its accuracy has yet to be fully tested.

Other reported drug-absorption studies include a systems approach to vaginal drug delivery and the influence of blood flow and solvent effects on i.m. drug absorption. Percutaneous drug absorption has been reviewed by Riegelman and Idson.

The advantages of intra-arterial drug infusions have been evaluated in some detail in terms of increased drug delivery and effectiveness in a particular target organ or tissue. The...