Abstract

Isotretinoin (13-cis-retinoic acid, 13cisRA) is widely used for the treatment of neuroblastoma and acne. It acts via regulating gene transcription through binding to retinoic acid receptors (RARs). Yet, the potential for isotretinoin to cause transcriptionally mediated drug-drug interactions (DDIs) has not been fully explored. We hypothesized that isotretinoin and its active metabolites all-trans-retinoic acid (atRA) and 4-oxo-13cisRA would alter the transcription of enzymes and transporters in the human liver via binding to nuclear receptors. The goal of this study was to define the DDI potential of isotretinoin and its metabolites resulting from transcriptional regulation of cytochrome P450 (CYP) and transporter mRNAs. In human hepatocytes (n=3), 13cisRA, atRA and 4-oxo-13cisRA decreased OATP1B1, CYP1A2, CYP2C9, and CYP2D6 mRNA and increased CYP2B6 and CYP3A4 mRNA in a concentration-dependent manner. The EC₅₀-values for OATP1B1 mRNA downregulation ranged from 2 - 110 nM with E_max ranging from 0.17 - 0.54-fold. Based on the EC₅₀ and E_max-values and the known circulating concentrations of 13cisRA and its metabolites after isotretinoin dosing, a 55% decrease in OATP1B1 activity was predicted in vivo. In vivo DDI potential was evaluated clinically in subjects dosed with isotretinoin for up to 20 weeks using coproporphyrin-I (CP-I) as an OATP1B1 biomarker. CP-I steady state serum concentrations were unaltered following two, eight or 16 weeks of isotretinoin treatment. These data show that isotretinoin and its metabolites alter transcription of multiple enzymes and transporters in vitro but translation of these changes to in vivo drug-drug interactions requires clinical evaluation for each enzyme.

Significance Statement Isotretinoin and its metabolites alter the mRNA expression of multiple CYPs and transporters in human hepatocytes suggesting that isotretinoin may cause clinically significant DDIs. Despite the observed changes in OATP1B1 mRNA in human hepatocytes no clinical DDI was observed when measuring a biomarker, CP-I. Further work is needed to determine whether these findings can be extrapolated to a lack of a DDI with CYP1A2, CYP2B6 and CYP2C9 substrates.