TY - JOUR T1 - A Mechanism-Based Mathematical Model of Aryl Hydrocarbon Receptor-Mediated CYP1A Induction in Rats Using β-Naphthoflavone as a Tool Compound JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2278 LP - 2285 DO - 10.1124/dmd.110.034421 VL - 38 IS - 12 AU - Emile P. Chen AU - Liangfu Chen AU - Yan Ji AU - Guoying Tai AU - Yuan H. Wen AU - Harma Ellens Y1 - 2010/12/01 UR - http://dmd.aspetjournals.org/content/38/12/2278.abstract N2 - β-Naphthoflavone (BNF) is a synthetic flavone that selectively and potently induces CYP1A enzymes via aryl hydrocarbon receptor activation. Mechanism-based mathematical models of CYP1A enzyme induction were developed to predict the time course of enzyme induction and quantitatively evaluate the interrelationship between BNF plasma concentrations, hepatic CYP1A1 and CYP1A2 mRNA levels, and CYP1A enzyme activity in rats in vivo. Male Sprague-Dawley rats received a continuous intravenous infusion of vehicle or 1.5 or 6 mg · kg−1 · h−1 BNF for 6 h, with blood and liver sampling. Plasma BNF concentrations were determined by liquid chromatography-tandem mass spectrometry. Hepatic mRNA levels of CYP1A1 and CYP1A2 were determined by TaqMan. Ethoxyresorufin O-deethylation was used to measure the increase in CYP1A enzyme activity as a result of induction. The induction of hepatic CYP1A1/CYP1A2 mRNA and CYP1A activity occurred within 2 h after BNF administration. This caused a rapid increase in metabolic clearance of BNF, resulting in plasma concentrations declining during the infusion. Overall, the enzyme induction models developed in this study adequately captured the time course of BNF pharmacokinetics, CYP1A1/CYP1A2 mRNA levels, and increases in CYP1A enzyme activity data for both dose groups simultaneously. The model-predicted degradation half-life of CYP1A enzyme activity is comparable with previously reported values. The present results also confirm a previous in vitro finding that CYP1A1 is the predominant contributor to CYP1A induction. These physiologically based models provide a basis for predicting drug-induced toxicity in humans from in vitro and preclinical data and can be a valuable tool in drug development. ER -