Assessment of Methods to Identify Sources of Interindividual Pharmacokinetic Variations

The advantages and limitations of the 2 most commonly used methods to investigate interindividual pharmacokinetic variations are reviewed. The first method is based on pharmacokinetic comparisons made after repeated administration of a model drug such as antipyrine, before, during and after imposition of a carefully controlled environmental perturbation. A principal virtue of the test is the use of each subject as a control. Subjects are usually under near basal conditions with respect to factors capable of altering hepatic drug-metabolising capacity. Exceedingly sensitive, the test yields highly reproducible results. It has been useful as a research tool in identifying environmental factors for which dose-response curves can be generated and compared. However, the test requires careful selection and control of subjects, and it may be hazardous to extrapolate results to subjects under different, non-basal, environmental conditions. This method most frequently involves antipyrine as the test compound, but other drugs can and have been used. The results disclose that many host factors that influence antipyrine disposition also affect the disposition of other drugs metabolised by hepatic mixed-function oxidases. Recent refinement of the antipyrine test involves measurement of the rate constant for formation of each of the 3 main metabolites of antipyrine. Sensitivity and specificity of the test are increased through examination of the effect of each factor on a separate hepatic cytochrome P-450. Due to the labouriousness of this procedure and its requirement for several days of urine collection from each subject, metabolite analysis will probably remain an experimental method not applicable for screening populations. The second method involves a particular model based on multiple regression analysis. Relying on correlations with historical data of a qualitative nature, previous applications of this method have been retrospective, rather than prospective. Several such correlations could not be confirmed in normal subjects under the conditions of a controlled prospective experiment. Thus, prospective studies need to be performed to check results obtained with this method. The model used appears to enjoy certain advantages, including speed, simplicity, and ease of execution. Since in all its previous applications only a single rate measurement has been performed in each subject, the method is more conveniently employed than the antipyrine test to screen large numbers of environmentally perturbed subjects, i.e. the method seems attractive under ‘real world’ conditions. Nevertheless, this method as used has disadvantages. In past applications no controls have been included and only parent drug, rather than metabolites, has been measured. Also, reproducibility of results in a given population has not been firmly established and since very few subjects are usually studied, compared with the large number of variables and environmental perturbations represented, it is dubious whether the subjects reliably reflect the much larger population from which they are drawn. This is because of the difficulty of defining quantitatively in each perturbed subject precisely how much each host factor contributes to the observed rate of drug elimination. The more environmentally perturbed the subjects selected for study, the more interindividual variation will probably occur in their response to drugs; the model used ignores these problems, and accordingly in such environmentally perturbed subjects, genetic factors have been concealed and inaccurately estimated. Any given environmental factor is considered by the model to produce similar pharmacokinetic effects in all subjects, whereas extensive interindividual variability in such responses occurs for which the model as used does not compensate.