XenoGesis has launched a new service where the intrinsic clearance and ‘top 3 metabolites’ are measured and identified simultaneously from a single experiment.
Traditionally, compounds are initially assessed for intrinsic clearance and T½ in cryopreserved hepatocytes. If a compound is highly metabolised, another study is frequently commissioned to understand exactly which parts of the molecule are subject to biotransformation. This key information is then shared and discussed with Medicinal Chemists and a strategy to reduce intrinsic clearance via either steric blocking, electronic effects or an isostere approach is agreed between the DMPK scientist and Medicinal Chemist. Whilst the approach works well, having to conduct two hepatocyte experiments, coupled with the required wait from the intrinsic clearance assays to read out, wastes valuable time and money in the design-synthesise-test cycle limiting the influence that metabolite identification could have on compound design.
This offering is designed to save time and cost for the client whilst adding extra value of having this information available for multiple compounds within a series. The benefit of this approach is to robustly inform the structure-metabolism relationship (SMR). An additional bonus of this service is the identification of possible new lead molecules that are metabolites of the parent compound.
As the DMPK/ADME properties of a drug define exactly what free-drug systemic, tissue and sub-cellular exposure are achieved, understanding and being able to predict this in preclinical species and man with confidence is essential to success.
For compounds that are metabolised by the liver (the majority), intrinsic clearance is the major predictor of unbound drug exposure in vivo that will drive efficacy.
Cryopreserved hepatocytes from all relevant species are the gold standard as they contain the full complement of all drug metabolizing enzymes and uptake transporters, along with a cell membrane.
The XenoGesis single experiment approach is a step-change with regards to efficiency, cost, project learning and application.
Contact a member of the team today to see how XenoGesis can accelerate your path to a quality candidate drug via the top 3 metabolite service.