Use of Immortalized Human Hepatocytes to Predict the Magnitude of Clinical Drug-Drug Interactions Caused by CYP3A4 Induction

• DOI: 10.1124/dmd.106.010132
• Publication Date: 2006-07-13T00:44:46Z
• Authors: Sharon L. Ripp; Jessica B. Mills; Odette A. Fahmi; Kristen A. Trevena; Jennifer L. Liras; Tristan S. Maurer; Sonia M. de Morais
• Keywords: Drug response

Cytochrome P4503A4 (CYP3A4) is the principal drug-metabolizing enzyme in human liver. Drug-drug interactions (DDIs) caused by induction of CYP3A4 can result decreased exposure to coadministered drugs, with potential loss efficacy. Immortalized hepatocytes (Fa2N-4 cells) have been proposed as a tool identify inducers. The purpose current studies was characterize effect known inducers on Fa2N-4 cells, and determine whether these vitro data could reliably project magnitude DDIs induction. Twenty-four compounds were chosen for studies, based previously published using primary hepatocytes. Eighteen had shown be positive induction, six negative In all 18 controls produced greater than 2-fold maximal 6 less 1.5-fold Subsequent conducted relationship between vivo response. approach relate (<i>E</i>_max EC₅₀ values) efficacious free plasma concentrations calculate relative score. This score then correlated decreases area under concentration versus time curve values object drugs (midazolam or ethinylestradiol) from clinical DDI studies. Excellent correlations (<i>r</i>² &gt;0.92) obtained, suggesting that cells used identification well prediction DDIs.