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High-quality services for screening of metabolism-related toxicity

4 April 2014

The drug metabolism can also form chemically reactive metabolites that may bind enzymes, proteins or nucleic acids, and thus cause unexpected drug-induced toxicity. The forming metabolites can also possess inhibiting properties towards cytochrome P450 enzymes (CYPs). Depending on the mechanism, this inhibition is typically referred as time-dependent inhibition (TDI) or mechanism based inhibition (MBI), and it may lead to over-exposure of co-administered drug due to drug-drug interactions, possibly by permanent inactivation of CYP enzymes.

We at admescope are proud to be undisputed leader in the field of reactive drug metabolites and metabolism related CYP inhibition. Due to our extensive R&D work in this field we can offer unique and/or hard-to-find services and a proof of our capabilities we also have several highly esteemed scientific publications. Admescope has also assays available for screening of cytotoxicity, genotoxicity and cardiotoxicity.


Reactivecreen is conducted using liver microsomes or S9 fraction in the presence of cofactors and stable isotope-labeled agents; GHS and KCN, to trap both soft and hard electrophiles. To guarantee supreme quality in data, highly sensitive UPLC/Q-TOF-MS is employed to obtain accurate mass data for identification of formed GSH or CN adducts.


Glucuronide-conjugation is most commonly considered as a detoxification route, but in the presence of carboxylic acid moiety in a parent drug or a metabolite, reactive acyl-glucuronide conjugates (AGs) can be formed. These conjugates can readily react with plasma and tissue proteins, and their chemical stability in various conditions is shown to correlate well with their toxicity. acylstabis an assay to assess the stability and reactivity of acyl-glucuronide metabolites in the liver microsomes or S9. Use of UPLC/TOF-MS analysis results high quality separations between isomeric AGs formed via acyl migration reaction, and also differentiates the disappearance by acyl migration or hydrolysis reaction. 


TDIscreen will reveal if NCE or its metabolites inhibit CYP enzymes over time, using a IC50-shift approach between pre-incubation with and without NADPH in human liver microsomes. The assay contains comprehensive cocktail for all major drug metabolizing CYP enzymes. LC/MS/MS is utilized to determine the level of metabolites formed. This assay can also be extended to include more detailed experiments to reveal kinetic inactivation parameters (kinact and KI), and/or dialysis-including inhibition experiments to confirm the covalent nature of interaction.