What is metabolic drug stability?

Metabolic stability refers to the susceptibility of compounds to biotransformation in the context of selecting and/or designing drugs with favourable pharmacokinetic properties. The utility of these systems to define the metabolic stability of compounds that is predictive of the human situation will be reviewed here.

Why is metabolic stability important?

Compound stability is an important factor to consider during the early stages of drug discovery. Our metabolic stability assays measure the intrinsic clearance (Clint) of a compound providing critical data needed to calculate other key pharmacokinetic parameters such as bioavailability and half-life (t1/2).

How do you increase metabolic stability?

One strategy for improving the metabolic stability of a compound is to reduce the overall lipophilicity (e.g. logP, and logD) of the structure. This is because the binding site of metabolizing enzymes is generally lipophilic in nature and hence these enzymes more readily accept lipophilic molecules.

How do you calculate unbound intrinsic clearance?

Intrinsic clearance (CLi) relates to hepatic extraction (E) and hence systemic clearance CLs and hepatic first-pass effect (F):[1]E=fu⋅CLi/fu⋅CLi+QH where fu is fraction unbound in blood and QH is liver blood flow.

What is microsomal stability?

Microsomal stability is one of Cyprotex’s in vitro ADME screening services. Cyprotex deliver consistent, high quality data with cost-efficiency that comes from a highly automated approach.

What are conjugation reactions?

Conjugation reactions are catalyzed by enzymes known as transferases. D. They involve a cofactor that binds to the enzyme in close proximity to the substrate and carries the endogenous molecule or moiety to be transferred.

What are highly extracted drugs?

It is defined as the fraction of drug removed from blood by the liver, and depends on 3 factors— the hepatic blood flow, the uptake into the hepatocytes, and the enzyme metabolic capacity. Examples of drugs with a high hepatic extraction ratio include propranolol, opiates, and lignocaine.

Are clearance and elimination the same?

Clearance is defined as ‘the volume of blood cleared of drug per unit time’. Drug elimination rate is defined as ‘the amount of drug cleared from the blood per unit time’ In first order kinetics, elimination rate is proportional to dose, while clearance rate remains independent of the dose.

What is microsomal assay?

The microsomal stability assay is primarily used to investigate Phase I metabolism using NADPH as the enzyme co-factor. However liver microsomes can also be used to study Phase II metabolism if the correct incubation conditions are used.

What are microsomal enzymes?

Microsomal enzymes are typically found in the endoplasmic reticulum of hepatocytes. Microsomes are fragments of endoplasmic reticulum and attached ribosomes that are isolated together when homogenized cells are centrifuged.

How are microsomal stability assays used in drug discovery?

High throughput in vitro microsomal stability assays are widely used in drug discovery as an indicator for in vivo stability, which affects pharmacokinetics. This is based on in-depth research involving a limited number of model drug-like compounds that are cleared predominantly by cytochrome P450 metabolism.

How is microsomal stability used in ADME screening?

Understand the metabolism of your compounds by using our microsomal stability assay to measure in vitro intrinsic clearance or to identify metabolites formed. Microsomal stability is one of Cyprotex’s in vitro ADME screening services.

How to predict overall microsomal stability in vitro?

The products of in vitro biotransformations utilizing microsomes were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS). The obtained experimental results are supported by density functional theory (DFT) calculations and model building based on the support vector machine (SVM) technique.

How are intrinsic clearance data obtained from microsomal stability assay?

Mean intrinsic clearance data for 13 compounds obtained using Cyprotex’s Microsomal Stability assay (error bars represent the standard deviation from quadruplicate incubations within each run of the assay). The graphs shows consistency of data both within the assay and between separate runs of the assay.