CYP Inhibition

Overview

Sekisui XenoTech's study design evaluates drug candidates as direct, time-dependent and metabolism-dependent inhibitors of CYP enzymes in human liver microsomes. Our design allows us to screen for inhibition due to the drug added to the test system as well as inhibition due to metabolites formed during preincubation. The design features low protein concentrations and short incubation times to minimize artifacts caused by protein binding, metabolic instability of the test article and excessive metabolism of the marker substrate. We offer various options for follow-up studies to support the further characterization of those drug candidates that are identified as potent direct or metabolism-dependent inhibitors (for example: Ki determinations, XTRA: Sekisui XenoTech's Reversibility Assay, KI/kinact determinations).
 

Assay Selection

Enzyme Substrate
CYP1A2 Phenacetin O-dealkylation
CYP2A6 Coumarin 7-hydroxylation
CYP2B6 Efavirenz 8-hydroxylation
CYP2B6 Bupropion hydroxylation
CYP2C8 Amodiaquine N-dealkylation
CYP2C8 Paclitaxel 6-hydroxylation
CYP2C9 Diclofenac 4´-hydroxylation
CYP2C19 S-Mephenytoin 4´-hydroxylation
CYP2D6 Dextromethorphan O-demethylation
CYP2E1 Chlorzoxazone 6-hydroxylation
CYP3A4/5 Testosterone 6β-hydroxylation
CYP3A4/5 Nifedipine oxidation
CYP3A4/5 Midazolam 1´-hydroxylation
CYP3A4/5 Atorvastatin ortho-hydroxylation
CYP4A11 Lauric acid 12-hydroxylation
 




























Test System

Sekisui XenoTech's inhibition assays are typically performed with pooled human liver microsomes (pool of 200). This allows the same pool of human liver microsomes (and often the same experimental conditions, e.g., microsomal protein concentrations and incubation time) to be used to study all CYP enzymes of interest.


Incubation Conditions

Protein concentration ≤0.1 mg/mL
Incubation time: 5 minutes
Pre-incubation time (in the presence and absence of NADPH): 30 minutes

Results

Direct, time-dependent and metabolism-dependent IC50 values are determined from seven concentrations of the drug candidate.


Follow-up Studies

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Discovery Plus™ Inhibition (Screen)
UGT Inhibition
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