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Metabolic Stability of Drugs

2018-03-01
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Compound stability is an important factor to consider during the early stages of drug discovery. We have a leading portfolio of compound stability services designed to help you understand the metabolic profile of your compounds.

The aim of metabolic stability study is measuring the disappearance rate of a chemical compound. The half-life, in vitro clearance measured from metabolic stability assay can be used to predict hepatic clearance, and also to evaluate dose, toxicity, oral bioavailability, etc. For instance, if a drug is rapidly metabolized when entering to the body, it may require more daily dosing to maintain its blood or tissue concentrations in order to get an ideal therapeutic effect. On the other hand, if a drug is slowly metabolized, the dose need to be adjusted and more preclinical toxicity tests should be conducted as long-time exposure may cause toxic build-up.

Many compounds with promising pharmacological characteristics never become drugs due to poor metabolic stability profiles. For example, a drug that is rapidly metabolized may not produce sufficient in vivo exposure levels or a drug that is slowly metabolized could remain in the body for extended periods leading to unwanted adverse effects.In order to provide accurate predictions of the stability of your compounds in various organs in the body, we offer a wide variety of in vitro test systems.All our assays can be ordered individually, combined or as a selection of key stability services provided in our drug candidate assessment packages to provide cost savings.

Metabolic Stability Studies

Liver Microsomal Stability

The liver is the main organ for drug metabolism in the body. Microsome, the liver subcellular fraction, is an important model for drug metabolism studies. It contains many drug metabolizing enzymes (like P450s, FMOs, and UGTs), easy to prepare, has long storing period, easy to adaptable to HTS, and can make donor pool from multiple donors to minimize the effect of interindividual variability. Medicilon provides liver microsomal stability assay which incubates microsomes with the test compound at 37°C followed by monitoring disappearance of the test compound. The results are characterized by UPLC/HR-MS/MS.

Hepatocyte Stability

Intact hepatocytes contain the cytochrome P450s (CYPs), non-P450 enzymes, and phase II enzymes such as sulfo- and glucuronosyltransferases. Therefore, hepatocyte assays can more broadly assess the overall cellular metabolism of the test compound than liver microsomal assay. Medicilon provides immortalized human liver cell line HepaRG for hepatocyte stability assays.

 

S9 Stability

S9 fraction (post-mitochondrial supernatant fraction) is another important model for drug metabolism studies. S9 fraction consists of both microsomal and cytosolic enzymes (SULT, GST, XO, ADHs, NATs) and it can be supplemented with cofactors such as UDPGA and PAPS to investigate Phase II metabolic pathways.

 

Recombinant Enzymes Stability

Medicilon uses mixture of expressed enzymes (e.g. CYP450s and UGTs) to identify which enzyme metabolizing isoforms are responsible for the metabolism of a test compound. Also, it is useful for identifying potential drug-drug interactions. This system is especially useful for studying highly stable compounds.

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