Does in vitro CYP down‐regulation translate to in vivo drug‐drug interactions? Preclinical and clinical studies with 13‐cis‐retinoic acid

Abstract

All‐trans‐retinoic acid (atRA) down‐regulates CYP2D6 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 (DDI). atRA, 13cisRA, and 4‐oxo‐13cisRA 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 13cisRA. However, the geometric mean AUC ratio for dextromethorphan between treatment and control was 0.822 indicating a weak induction of dextromethorphan clearance following 13cisRA treatment. Similarly, in mice treatment with 4‐oxo‐13cisRA 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. This data suggests that in vitro CYP down‐regulation may not translate to in vivo DDIs, and better understanding of the mechanisms of CYP down‐regulation is needed.

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