In vitro metabolism

Cyprotex is a specialist provider of ADME and PK services and provide a range of in vitro drug metabolism assays. 

Metabolic stability

A drug that is rapidly metabolized may require multiple daily dosing or continuous infusion to maintain a concentration in the bloodstream or target organ that is sufficient to elicit a therapeutic effect. However, a slowly metabolized drug may remain in the body for long periods, causing toxic build-up. For more background information on the significance of stability studies in early ADME and DMPK see our online ADME Guide.

Cyprotex provide microsomal stability, hepatocyte stability, S9 stability, plasma stability and recombinant enzyme stability assays to determine the extent of metabolic stability in vitro. If required, a comprehensive metabolite profiling and identification service is also available to elucidate metabolites formed in the stability studies. We can perform microsomal binding studies to understand the free concentration available in the microsomal incubations.

For compounds which have a particularly low clearance, accurate extrapolation of the in vitro intrinsic clearance to the in vivo situation can be challenging using the standard methods. We have two options for addressing low clearance, one using the HµREL co-culture model (offered through Cyprotex) and the other using plated human hepatocytes with a matrix overlay (offered through Cyprotex's parent company, Evotec). Evotec can also assess hepatic uptake using the media loss assay which takes into account the active uptake into hepatoocytes by drug transporters.

Drug-drug interactions (DDI)

The most common types of metabolic drug–drug interactions are the inhibition and induction of the drug metabolizing enzymes. These interactions can cause increased or decreased drug exposures when two or more drugs are co-administered. For example, cytochrome P450 inhibition (CYP450) may increase the plasma levels of co-administered drugs leading to toxicity. Conversely, if a CYP450 enzyme is induced it may increase the metabolism of the co-administered compound; this can reduce plasma levels resulting in decreased efficacy or an increased formation of a toxic metabolite. For more background information on DDI studies, see our online ADME Guide and our DDI regulatory guidance booklet.

Cyprotex provide a range of services to investigate drug-drug interactions including cytochrome P450 inhibition (IC₅₀ and K_i determination) , time dependent inhibition (single point, IC₅₀ shift, k_inact/K_I), cytochrome P450 induction (catalytic activity, mRNA assessment and relative induction score), PXR and AhR nuclear receptor activation and UGT inhibition.

Investigating if any of the main CYP isoforms are involved in the in vitro metabolism of a drug is also important in determining whether a clinical DDI study is necessary. To this end, Cyprotex provide a cytochrome P450 and UGT reaction phenotyping service using recombinant enzyme.