Metabolism is the process of biotransformation of both endo- and xenobiotics, including drugs. In fact, for 75% of all drugs, metabolism represents the major route of clearance. The majority of drugs that undergo extensive metabolism are metabolized by the enzymes belonging to the cytochrome P450 families 1, 2 and 3, with major contributions from CYP3A4/5 (37% of drugs) followed by CYP2C9 (17%), CYP2D6 (15%), CYP2C19 (10%), CYP1A2 (9%), CYP2C8 (6%), and CYP2B6 (4%). These CYP450 enzymes are mainly mediating oxidative reactions. Beyond the CYP450 enzymes, other oxidative enzymes (e.g. aldehyde oxidase, dehydrogenases, xanthine oxidoreductase) or enzymes mediating hydrolysis, reduction, and conjugation can also play a role in metabolic clearance of drugs.
If substrate of drug metabolizing enzymes, the metabolic clearance of a drug depends on the activity and abundance of drug-metabolizing enzymes. Changes in the clearance rate of metabolism of a drug may move systemic exposure outside of the therapeutic window, thereby leading to a loss of efficacy or induction of toxicity. Both activity and expression of these enzymes can be affected by genetic variance, environmental factors and/or drug-drug interactions (DDI).
Drug-drug interactions occur when two (or more) drugs are co-administered and the inhibition or induction potential of one drug (perpetrator) affects the metabolic clearance of the other drug (substrate).
That metabolism-based drug-drug interactions (DDI) via inhibition or induction may pose a large safety concern is exemplified by the fact that various drugs that have been withdrawn from the market or their use was restricted by strict prescribing restrictions due to severe toxicities arising from metabolic DDIs. It is therefore crucial to assess the potential of an investigational drug to cause (inhibitor or inducer, perpetrator) or be affected (substrate, victim) by such DDIs. Consequently, regulatory agencies such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) or the Japanese Pharmaceuticals and Medicines Agency (PMDA) require that potential drug interaction risks be investigated before large scale clinical trials are conducted.
Potential drug-drug interactions between drug metabolizing enzymes and candidate drugs are therefore usually assessed during the lead-to-development stage, before clinical trials. These investigations are routinely done via in vitro methods including the study of metabolism in recombinant enzymes, liver microsomes (LM), liver S9 fractions, and/or hepatocytes. The availability of these models for different preclinical species (mouse, rat, dog, monkey etc.) allow for the study of species differences and understand the metabolic behavior of new compounds, which may consequently improve human prediction an safety based on in vivo animal studies.
Each of these systems have their pros and cons, and limit of use. In the links below we provide further information on these different assay types offered at SOLVO.