Receptor Activation Screening Services are available using Puracyp's proprietary cell lines. Identification of NCEs that activate human, rat or monkey PXR and subsequently induce CYP3A are available. In addition, activation of PXR and induction of P-glycoprotein can be evaluated in either intestinal or hepatic cells. The activation of AhR and induction of CYP1A2 can be assessed.

Reporter gene results (luciferase activity) are normalized to viable cell number. Two basic study designs are offered: benchmark and EC₅₀. In the benchmark study design, the ability of new chemical entities (NCE) at three concentrations to activate the receptor studied is compared to controls exhibiting potent, moderate and weak activation. The potency of the NCE is rated against the controls. With EC₅₀, the NCE is compared to three standards at up to 10 concentrations. An example of a report is shown.

Included in the study cost are three controls, and cell viability (reports toxicity of the parent NCE without metabolism). Results are standardized to the number of live cells. Study turnaround time is 14 business days from receipt of compounds and PO number. Seven business day turnaround is available for an additional fee.

Cytotoxicity Screening Services

These services are used to determine the toxicity of NCE or their metabolites following either CYP3A4 or CYP1A2 metabolism. These services will predict cellular toxicity of a parent compound and or its metabolite. An example demonstrating toxicity produced by CYP3A4 metabolism of diclofenac and troglitazone are presented.

Whole Cell Inhibition Screening Services

To assess the ability of NCE to inhibit metabolism by CYP3A4 or CYP1A2 is important information in predicting drug-drug interactions. An advantage to performing inhibition studies in whole cells is that results can more readily predict inhibition that might occur in vivo.

An example of results generated with prototypical inhibitors and their IC₅₀ values are shown.

Mechanistic and Species Comparison Studies

Puracyp's cell lines can not only identify compounds that induce drug metabolizing enzymes and transporters, but can also determine the mechanism involved. Because Puracyp possesses rat, monkey and human PXR, species comparisons can be made with regards to the activation of PXR and subsequent induction of PXR regulated genes.

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