Does In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug‐Drug Interactions? Preclinical and Clinical Studies With 13‐cis‐Retinoic Acid. Issue 4 (20th March 2019)

• Record Type: Journal Article
• Authors: Stevison, Faith; Kosaka, Mika; Kenny, Jane R.; Wong, Susan; Hogarth, Cathryn; Amory, John K.; Isoherranen, Nina
• Is Part Of: Clinical and translational science. Volume 12:Issue 4(2019)
• Page Start: 350
• Page End: 360
• Publication Date: 2019-03-20
• Subjects: Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; 616.027
• DOI: 10.1111/cts.12616
• Languages: English
• ISSNs: 1752-8054

Abstract

Abstract : All‐trans ‐retinoic acid ( at RA) downregulates cytochrome P450 (CYP)2D6 in several model systems. The aim of this study was to determine whether all active retinoids downregulate CYP2D6 and whether in vitro downregulation translates to in vivo drug–drug interactions (DDIs). The retinoids at RA, 13 cis RA, and 4‐oxo‐13 cis RA all decreased CYP2D6 mRNA in human hepatocytes in a concentration‐dependent manner. The in vitro data predicted ~ 50% decrease in CYP2D6 activity in humans after dosing with 13 cis RA. However, the geometric mean area under plasma concentration‐time curve (AUC) ratio for dextromethorphan between treatment and control was 0.822, indicating a weak induction of dextromethorphan clearance following 13 cis RA treatment. Similarly, in mice treatment with 4‐oxo‐13 cis RA–induced mRNA expression of multiple mouse Cyp2d genes. In comparison, a weak induction of CYP3A4 in human hepatocytes translated to a weak in vivo induction of CYP3A4. These data suggest that in vitro CYP downregulation may not translate to in vivo DDIs, and better understanding of the mechanisms of CYP downregulation is needed.