Assessment of Methods to Identify Sources of Interindividual Pharmacokinetic Variations

Abstract

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.(ABSTRACT TRUNCATED AT 400 WORDS)

Polymorphism of theophylline metabolism in man.

“…Confusion occasionally arises between the numerical value of a correlation coefficient and the predictability of that correlation. They are not synonymous: the predictability of one variable based on its correlation to another is not determined by r but by r2 (51), a much lower number than r. The widespread practice of using correlations as proof of a pharmacological relationship, rather than as a clue to design and perform a well-controlled experiment that adequately tests a hypothesis, should be discouraged (52,53).…”

Genetic aspects of the polymodally distributed sulphoxidation of S‐ carboxymethyl‐L‐cysteine in man.

“…Exploration of the likelihood surface of the data for uni-or multimodality indicated that the model with the best fit had two modes and raised the possibility that this phenomenon may be under the control of two alleles of major effect at a single autosomal locus, the variation within the modes being due to other genes with comparatively small effects and to other environmental influences (Vesell & Penno, 1983). However, a multimodal distribution only provides very preliminary evidence for a segregating major gene and although the data obtained from the family studies can be interpreted to support the assumption of a genetic mode of inheritance of the impaired sulphoxidation trait, final proof of its existence must await the isolation and characterisation of the specific gene products.…”

Ibuprofen disposition in obese individuals

“…It is possible that this enzymatic activity is increased in obese individuals, since there is now considerable evidence that subspecies of hepatic cytochrome P-450 may be selectively induced or inhibited with no change in the activity of other subspecies (29). Furthermore, the specific enzyme systems that mediate ibuprpfen biotransformation are not well identified; however, they are resistant to inhibition by cimetidine, which, for all substrates studied to date, has uniformly inhibited cytochrome P-450-mediated drug biotrarisformations in vivo in humans (14).…”