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Cytochrome P450 Induction Assay

Creative Animodel has a brilliant history of offering a portfolio of high-quality pharmaceutical contract services, which have been well received by global clients. A group of experienced experts and advanced technical platforms enhance our capabilities to create the edge-cutting cytochrome P450 induction assay service in compliance with the criteria of FDA or EMA guidelines.

Cytochrome P450 (CYPs) family plays an important part in metabolism of drugs. And each CYP isoform is responsible for catalytic activities of a broad spectrum of substrates. When more than 2 drugs are co-administered, there is a possibility of drug-drug interactions (DDIs). According to FDA and EMA guidelines, the interactions of multiple drugs should be investigated, especially those involved in multidrug therapy. Because DDIs may alter the pharmacokinetics of drugs or their metabolites and both CYP inhibitor or inducer are not desirable. Two major issues are associated with CYP induction: an induction of reactive metabolites and a reduced therapeutic efficacy of comedications.

The Working Principle of Cytochrome P450 Induction Assay

Cytochrome P450 induction assessment is a powerful tool at early drug discovery stage to develop drugs that are not prone to inducing CYP enzymes. Among in vitro models for CYP induction assessment, primary human hepatocytes are probably the most prominent one. CYP1A2, CYP2B6 and CYP3A4 are subjected to assessments on mRNA level and/or catalytic activity according to FDA guidelines. Autoinduction and the mediation of nuclear receptor are two major mechanisms of CYP induction. Three nuclear receptors, including hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR) respectively transcriptionally activate CYP1A2, CYP2B6 and CYP3A4 through the mediation of drug-induced changes at the expression level of CYP enzymes. Methods like fluorometric probe substrates for catalytic activities, LC-MS/MS for probe metabolite quantification and qRT-PCR for relative expression levels, work together to fully determine CYP activity.

Figure 1. The schema of PXR mediated induction of CYP3A4.

Advantages of Cytochrome P450 Induction Assays by Creative Animodel

• Assays are established in compliance with FDA guidelines. For example, at least three donors of cryopreserved human hepatocytes are needed.
• The mRNA expression analysis and catalytic activity detection enable a sensitive and reliable understanding of DDIs. And negative control and positive control groups are set up to avoid false positive and false negative results.
• More than three key CYP enzymes (including CYP1A2, CYP2B6 and CYP3A4 ) are investigated. Other customized induction studies on liver enzymes, such as CYP2C and UGT, or transporters are also provided to meet your specific demands.
• State-of-the-art technical platforms are available, including LC-MS/MS for compound quantification and qRT-PCR for mRNA expression levels detection.
• Data analysis is performed by an experienced expert team.

Figure 2. CYP3A4 mRNA levels induced by rifampicin in primary human hepatocytes.

Creative Animodel is a professional custom service provider specialized in pharmaceutical industry and constantly delivers high-quality data with the flexibility to suit specific customer requirements. Creative Animodel is always the best partner for your drug discovery.

1. Lin, J.H. CYP induction-mediated drug interactions: in vitro assessment and clinical implications. Pharmaceutical research. 2006, 23(6): 1089-1116.
2. FDA Guidance for Industry: drug interaction studies - study design, data analysis, and implications for dosing and labeling recommendations, draft guidance, February 2012.

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