Pelkonen, O; Mäenpää, J; Taavitsainen, P; Rautio, A; Raunio, H
Detailed knowledge of metabolism of drugs is crucial for two main reasons.
First, metabolism determines to a large extent pharmacokinetic behaviour, interindividual variability and interactions of a drug, all matters of great importance
in drug treatment. Second, differences in metabolism are also often behind the
difficulties in the extrapolation from animals to man, which is a serious obstacle in drug testing and development.
There is a large number of factors affecting drug metabolism and they are usually classiffied into genetic and non-genetic host and environmental factors. In the last category, chemical exposures, including drug treatment, occupational exposure to chemicals or environmental pollution can lead either to induction or inhibition of drug metabolism.
Induction is defined as the increase in the amount and activity of a drugmetabolizing
enzyme, which is a long-term (hours and days) consequence of a chemical exposure. Inhibition of drug metabolism in general may mean either an
acute decrease of metabolism of a particular substrate by another simultaneously
present chemical or a time-dependent decrease in the amount of a drug-metabolizing
enzyme by several factors, such as a chemical injury or a disease process. In this
review, we will deal only with interactions at the level of enzymes. Previously, the study of induction and inhibition of drug metabolism was largely
empirical and phenomenological, and prediction beyond the compounds under
study was very difficult, if at all possible. During the past decade, however, and
particularly as a consequence of the detailed knowledge obtained about cytochrome
P450 (CYP) enzymes, both induction and inhibition can be understood on a detailed
mechanistic basis and the predictability of pharmacological and toxicological consequences has become possible.
As to clinical consequences of induction and inhibition, the nature of the products determine the outcome. If the reaction to be studied leads to inactive product(s), induction results in attenuation and inhibition results in exaggeration of the effects of a drug. If the product is active, either pharmacologically or
toxicologically, the reverse outcome is observed. This review covers the phenomena of induction and inhibition of human CYPs and concentrates upon quantitative aspects of in vitro and in vivo studies. This approach is hoped to provide a background for quantitative extrapolation of results
obtained from in vitro experimental systems to the in vivo situation, both for
induction and inhibition.