Open AccessDoes In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug‐Drug Interactions? Preclinical and Clinical Studies With 13‐ cis ‐Retinoic Acid
Author(s) -
Stevison Faith,
Kosaka Mika,
Kenny Jane R.,
Wong Susan,
Hogarth Cathryn,
Amory John K.,
Isoherranen Nina
Publication year - 2019
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12616
Subject(s) - downregulation and upregulation , in vivo , dextromethorphan , pharmacology , retinoic acid , cyp3a4 , cyp2d6 , cytochrome p450 , in vitro , chemistry , drug , biology , biochemistry , enzyme , gene , microbiology and biotechnology
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 CYP 2D6 and whether in vitro downregulation translates to in vivo drug–drug interactions ( DDI s). The retinoids at RA , 13 cis RA , and 4‐oxo‐13 cis RA all decreased CYP 2D6 mRNA in human hepatocytes in a concentration‐dependent manner. The in vitro data predicted ~ 50% decrease in CYP 2D6 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 CYP 3A4 in human hepatocytes translated to a weak in vivo induction of CYP 3A4. These data suggest that in vitro CYP downregulation may not translate to in vivo DDI s, and better understanding of the mechanisms of CYP downregulation is needed.