PT - JOURNAL ARTICLE AU - Anna L Blobaum AU - Frank W Byers AU - Thomas M Bridges AU - Charles W Locuson AU - P Jeffrey Conn AU - Craig W Lindsley AU - J Scott Daniels TI - A Screen of Approved Drugs Identifies the Androgen Receptor Antagonist, Flutamide, and its Pharmacologically Active Metabolite, 2-Hydroxy-Flutamide, as Heterotropic Activators of CYP 3A In vitro and In vivo AID - 10.1124/dmd.115.064006 DP - 2015 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.115.064006 4099 - http://dmd.aspetjournals.org/content/early/2015/08/11/dmd.115.064006.short 4100 - http://dmd.aspetjournals.org/content/early/2015/08/11/dmd.115.064006.full AB - Once thought to be an artifact of microsomal systems, atypical kinetics with cytochrome P450 (CYP) enzymes have been extensively investigated in vitro and found to be substrate and species-dependent. Building upon increasing reports of heterotropic CYP activation and inhibition in clinical settings, we screened a compound library of clinically-approved drugs and various probe compounds in order to identify the frequency of heterotropism observed with different drug classes and the associated CYP enzymes thereof (1A2, 2C9, 2D6, and 3A4/5). Results of this screen revealed that the prescribed androgen receptor antagonist, flutamide, activated the intrinsic midazolam hydroxylase activity of CYP3A in human hepatic microsomes (66%), rat and human hepatocytes (36% and 160%, respectively), and in vivo in male Sprague Dawley rats (> 2-fold, combined AUC of primary rat in vivo MDZ metabolites). In addition, a screen of the pharmacologically active metabolite, 2-hydroxy-flutamide, revealed that this principle metabolite increased CYP3A metabolism of midazolam in human microsomes (30%) and hepatocytes (110%). Importantly, both flutamide and 2-hydroxy-flutamide demonstrated a pronounced increase in the CYP3A-mediated metabolism of commonly paired medications, nifedipine (antihypertensive) and amiodarone (antiarrhythmic), in mutli-species hepatocytes (100% over baseline). These data serve to highlight the importance of appropriate substrate- and in vitro system-selection in the pharmacokinetic modeling of atypical enzyme kinetics. In addition, the results of our investigation have illuminated a previously undiscovered class of heterotropic CYP3A activators and have demonstrated the importance of selecting commonly paired therapeutics in the in vitro and in vivo modeling of projected clinical outcomes.