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CYP Inhibition

• CYP inhibition is one of the most relevant mechanism of drug-drug interactions
• Direct inhibition using N-in-one or individual CYP assay

• Time-dependent inhibition (TDI); caused by reactive/inhibitory metabolite
• Using liver microsomes, recombinant CYP enzymes or human hepatocytes
• Analysis with LC/MS/MS

Inhibition of cytochrome P450 (CYP) enzymes by a new chemical entity (NCE) may decrease the metabolism of co-medicated drugs. We offer assays for individual enzymes as well as a cocktail approach to determine inhibition towards multiple enzymes in the same incubation. Liver microsomes are recommended for high-throughput screenings and for mechanistic approach. Alternatively for systematic approach, human hepatocytes can be used to determine the CYP inhibition potential of the NCE in the cellular environment.

Screening assays are performed with up to eight cytochrome P450 enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4) with twelve probe reactions. Direct inhibition assay delivers IC50 values, as well as tentative Ki values towards each CYP enzyme. TDI assay results in direct and shifted IC50 values for each CYP enzyme.

More comprehensive single enzyme assays allow accurate Ki determination using multiple concentrations of a drug candidate and substrates. In the case of TDI, the assay delivers inactivation kinetic parameters maximal inactivation rate (kinact) and concentration at 50 % inactivation rate (KI).