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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.

clinical and translational science

Does  In Vitro  Cytochrome P450 Downregulation Translate to  In Vivo  Drug‐Drug Interactions? Preclinical and Clinical Studies With 13‐ cis ‐Retinoic Acid