The state of enzymatic systems involved in drug biotransformation represents an important factor in pharmacokinetic and/or pharmacodynamic variability. The changes in the state of enzymatic systems may be qualitative and quantitative. Qualitative changes are commonly due to impairments in the state of the enzymatic systems, genetically pre-determined (enzymopathies). Quantitative changes may evolve in two directions: either towards the stimulation of enzyme activity (enzyme induction) or the reverse, a reduction in enzyme activity (enzyme inhibition). The pharmacological consequences of both phenomena are quantitative and refer to the modification of intensity and/or duration of the pharmacological effect of the drug, the modification of t1/2 and biotransformation rate, the appearance of adverse reactions of overdosing, and therapeutic inefficacy. In this chapter, both enzyme induction and enzyme inhibition are examined closely, with an emphasis on the cytochrome P450 system.

Many examples are quoted to illustrate these effects and their general impact. An extensive discussion of the role of other factors affecting drug biotransformation follows. Recognizing that there is much interaction between them, these factors are systematically treated under the categories of internal and external factors. The present chapter deals with some of the internal factors that have direct implications for the cytochrome levels/activity, namely the dietary factors, comprising macro- and micronutrients, as well as tobacco smoking (considered also as adietary component since it is inhaled deliberately). Under these factors are also discussed the so-called non-dietary factors, such as pyrolysis products (compounds normally formed during cooking) and various food additives.

Induction is defined as an increase in enzyme activity associated with an increase in intracellular enzyme concentration. From a genetic point of view, this increase in enzymes’ protein is usually caused by an increase in transcription of the associated gene. The stimulation of enzyme activity represents a process of temporal, adaptive increase in the concentration of a specific enzyme, due either to an increase in its rate of synthesis, or in a decrease of its degradation rate. The direct consequence is an accelerated rate of biotransformation of both endogenous compounds and xenobiotics, by co-administration of another compound, designated as an inducer.

 The inducer will modify drug metabolism in different ways (either qualitatively or quantitatively) and it is therefore expected to alter the pharmacological effects of drugs (increase in the metabolism of the drug involved in interaction, and decrease in the quantity of drug available for pharmacological activity). In order for this to take place, 1-2 weeks are usually needed, the process being an adaptive, temporal one, as indicated above. Inductive properties may be displayed by compounds with quite different chemical structures, pharmacological actions, or even different toxicities. Drugs of abuse are also known to induce gene expression. The pharmacodynamic and pharmacotherapeutic consequences are reflected by a decrease in pharmacodynamic activity, and hence inefficacy at the usual therapeutic doses. As a first conclusion, we may therefore emphasise that enzyme induction contributes to inter- and intraindividual variation in drug efficacy and potential toxicity associated with drug-drug interactions.

Best Regards,
Nancy Ella
Associate Managing Editor
Drug Designing: Open Access