Isotretinoin and its Metabolites Alter mRNA of Multiple Enzyme and Transporter Genes In Vitro, but Downregulation of Organic Anion Transporting Polypeptide Does Not Translate to the Clinic

Abstract

Isotretinoin ] is widely used for the treatment of neuroblastoma and acne. It acts via regulating gene transcription through binding to retinoic acid receptors. 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-transretinoic 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 and transporter mRNAs. In human hepatocytes (n 5 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 EC 50 values for OATP1B1 mRNA downregulation ranged from 2 to 110 nM, with maximum effect (E max ) ranging from 0.17-to 0.54-fold. Based on the EC 50 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 participants dosed with isotretinoin for up to 32 weeks using coproporphyrin-I (CP-I) as an OATP1B1 biomarker. CP-I steady-state serum concentrations were unaltered following 2, 8, 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 STATEMENTIsotretinoin and its metabolites alter the mRNA expression of multiple cytochrome P450s (CYPs) and transporters in human hepatocytes, suggesting that isotretinoin may cause clinically significant drug-drug interactions (DDIs). Despite the observed changes in organic anion transporting polypeptide 1B1 (OATP1B1) mRNA in human hepatocytes, no clinical DDI was observed when measuring a biomarker, coproporphyrin-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.

Effect of isotretinoin on CYP2D6 and CYP3A activity in patients with severe acne

“…A previous study showed that UGT2B isoforms, including UGT2B4, UGT2B7, UGT2B15 and UGT2B17, are primarily responsible for the glucuronidation of DX to dextrorphan‐O‐glucuronide, suggesting the change in urinary MR may be due to induction of these UGTs 40 . UGT1A1 was found to be induced by approximately 2‐fold with treatment with retinoids (30 μM at RA, 13‐ cis RA or 4‐oxo‐13‐ cis RA) in human hepatocytes 41 . Another in vitro study indicated that vitamin A (100 μM) competitively inhibits UGT1A1, UGT2B4, UGT2B7 and UGT2B15 activity 42 .…”

“…40 UGT1A1 was found to be induced by approximately 2-fold with treatment with retinoids (30 μM atRA, 13-cisRA or 4-oxo-13-cisRA) in human hepatocytes. 41 Another in vitro study indicated that vitamin A (100 μM)…”