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A Simple Murine Model for Monitoring Cyp3a Induction and Inhibition In Vivo

Part # PS347

Abstract

James J. Cali, Dongping Ma and Andrew Niles
Promega Corporation, 2800 Woods Hollow Rd, Madison, WI 53711

Cytochrome p450 enzymes (CYPs) are prominent drug metabolizers that play a mechanistic role in adverse drug interactions in humans. In vitro biochemical and cell based CYP assays are generally predictive of in vivo drug interactions caused by CYP inhibition or induction. However, these predictions can be made with greater confidence when in vitro data is confirmed in an animal model. To this end we set out to establish a simple in vivo test for monitoring induction and inhibition of CYP3A enzymes, the most prominent drug metabolizing CYPs. We used the CYP3A selective substrate luciferin isopropyl acetal (luciferin-IPA) as a probe in wt FVB/N mice. Cyp3a enzymes selectively convert luciferin-IPA to a luciferin ester that can be detected with a luciferase formulation by luminometry. Luciferin-IPA was administered by IP injection and its luciferin ester metabolite accumulated in urine after renal elimination in dose-dependent quantities. This was measured by simply mixing urine samples with a luciferase formulation that produces light in proportion to the amount of luciferin ester present. The initial rate of metabolite appearance reflects a basal Cyp3a conversion rate. Pretreatment of the mice with Cyp3a inducers substantially enhanced the basal elimination rate, and a Cyp3a inhibitor reduced it. Here we report data to demonstrate the utility of luciferin-IPA as a probe for predicting the impact of drugs on Cyp3a activity in vivo by a simple urinalysis assay.

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