Induction

Induction has been defined as an increased level of enzyme gene expression (see 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs), and hence an increase in enzyme activity, resulting from exposure to a xenobiotic or endogenous components.87

The consequences are modifications in exposure to the drug (decrease) and its metabolites (increase) leading to potential changes of the efficacy profile of the drug (duration and intensity of action) or to its safety profile (reduced therapeutic margin). This is the case of the well-known interaction between oral contraceptives and rifampicin where the bioavailability of the former decreased by 42% due to induction of CYP3A4 by rifampicin, resulting in the loss of contraceptive efficacy.87 If both parent drug and major metabolites have the same pharmacological activity, then the pharmacological effect of the induction is reduced although the pharmacokinetics of both parent drug and metabolites have changed. This has been observed for the induction of alprenolol by pentobarbital.88

In addition, the induction may enhance the formation of reactive metabolites resulting in potential adverse reactions. The timescale of an induction and an inhibition is somewhat different. Induction processes, at the level of an organism, are not as immediate as inhibition mechanisms. They involve fewer isozymes, affecting only the inducible ones (principally CYP1A1-1A2, CYP2C9, CYP2E1, and CYP3A4).

The prime concern is the induction potential of an NCE able to affect the metabolism of coadministered compounds. On the other hand known inducers can also affect the metabolism of an NCE. For the latter case the information on the identity of the enzymes involved in the metabolism of an NCE is crucial to evaluate potential impacts.

Evaluation of the induction potential of a drug has been a weak point in early screening programs, carried out only for specific projects in which induction was known to represent a potential issue.

Strategies for evaluating the induction potential of drug candidates have often been, and still are, based on ex vivo animal liver analyses obtained from toxicological studies.31 However, with regard to the number of animals, amount of compound, and time required, they have proven to be inadequate for early screening. In addition, scaling results from animals to humans is unreliable due to interspecies differences89 in metabolizing enzymes and their regulation factors (such as nuclear receptor CAR, PXR, or AhR).87

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