Metabolic stability refers to the susceptibility of compounds to biotransformation and therefore influences oral bioavailability and systemic half-life of a compound, which in turn, affect its safety and efficacy profiles. As the major elimination pathway for most drugs, metabolism is achieved via two major enzyme reactions within the liver, Phase I and Phase II reactions.
Metabolic stability is often assessed in-vitro in liver microsomes, hepatocytes, and/or S9 fractions. After the incubation of compound(s) in the selected system (usually liver microsomes), samples are collected at different time points. Then remaining parent will be quantified, followed by calculation of half-life (T1/2) and intrinsic clearance (Clint).
3D BioOptima can provide metabolic stability studies of compounds in liver microsomes, hepatocytes, and S9 fractions.
The 2008 FDA CDER Guidance for Industry, Safety Testing of Drug Metabolites (MIST) highlighted the need to consider the contribution of metabolites to overall toxicity as early as possible in the drug development process. In vitro metabolite characterization is an early step toward meeting the agency's needs.
Using the state-of-the-art instrumentation (API 5500 QTRAP and Q-TOF MS) and software, our experienced analytical scientists can perform appropriate metabolic profiling across multiple species with comprehensive metabolite structural elucidation.
Understandingwhich enzymes are involved in the metabolism of a drug is important inpredicting the propensity towards interindividualvariability due to polymorphisms in enzyme expression and the tendency fordrug-drug interactions.
3DBioOptimaprovides reaction phenotyping (i.e., drug metabolizing enzyme identification)studies for CYPs and UGTs based on two approaches (i.e., chemical inhibitionand recombinant enzyme metabolism).
The metabolic clearance of a drug (victim) can be increased and its efficacy reduced, if it is co-administered with a second drug (perpetrator) that up-regulates (or induces) the enzyme responsible for the metabolism of the victim. The increased clearance may comprise the therapeutic effectiveness or safety issue of the victim drug.
3D BioOptima offers fit-for-purpose studies of CYP induction based on assessment at activity and/or mRNA expression levels.
Clearance of a drug (victim) by a particular CYP isoform can be impaired if it is administered with a second drug (perpetrator) that inhibits the CYP isoform. The primary purpose of evaluating drugs as inhibitors of certain CYPs is to determine their perpetrator potential before advancing a compound to a later stage.
Using the selected probe substrates and specific inhibitors of CYPs, 3D BioOptima provides a range of services to investigate the potential and/or potency of compounds as CYP inhibitors.
