Determining the Effect of Isotretinoin on CYP2D6 and CYP3A4 Activity in Patients with Severe Acne

Abstract

Cytochrome P450 2D6 (CYP2D6) and 3A4 (CYP3A4) are critical enzymes involved in the metabolism of commonly used drugs. There are high inter-individual variabilities in CYP2D6 drug-metabolizing activities, majorly caused by genetic polymorphism and transcriptional regulation. Previous in vitro and preclinical in vivo studies have shown the CYP2D6 expression was regulated by small heterodimer partner (SHP) as a transcriptional repressor via interacting with hepatic nuclear factor (HNF) 4α. Investigating potential drug-drug interactions resulting from CYP2D6 downregulation in vitro and in vivo is necessary. Isotretinoin (13-cis-retinoic acid) is an FDA-approved drug used to treat severe, recalcitrant, nodulocystic acne and neuroblastoma. Previously 13-cis-retinoic acid, its isomer, all-trans-retinoic acid, and its metabolite 4-oxo-13-cis-retinoic acid were shown to downregulate CYP2D6 expression and induce SHP expression in vitro, but the effect was not observed in healthy males. CYP3A4 was shown to be induced after treatment with isotretinoin in vitro and in vivo. A larger participant size and mixed sexes were necessary to fully capture the role of retinoid impact on CYP2D6 and CYP3A4 regulation. In this study, thirty-three participants (22 females and 11 males) who required isotretinoin treatment for acne were recruited. There were two study time points, including pre-isotretinoin control and after isotretinoin initiation for at least a week. Dextromethorphan plasma and urinary metabolic ratios were compared between two study time points to indicate changes in CYP2D6 and CYP3A4 activity after isotretinoin administration. No statistically significant difference was reported in CYP2D6 activity, while a weak induction in CYP3A4 activity was observed after isotretinoin administration. Future investigation on the mechanism of CYP2D6 regulation by retinoids in humans is necessary.