Isoherranen, NinaLaFrance, Jeffrey Matthew2024-10-162024-10-162024-10-162024LaFrance_washington_0250O_26995.pdfhttps://hdl.handle.net/1773/52599Thesis (Master's)--University of Washington, 2024Isotretinoin is an FDA approved treatment for severe cystic acne and neuroblastoma and has been deployed in several non-FDA approved treatments of various cancers.1-5 Cortisol (COL) and Cortisone (CON) are metabolized to their 6β-hydroxy metabolites primarily by CYP3A4.6 Cortisol and 6β-hydroxycortisol (6β-OHCOL) are converted by 11β-HSD type 2 to cortisone and 6β-hydroxycortisone (6β-OHCON) respectively. Inversely, cortisone and 6β- hydroxycortisone are converted to cortisol and 6β-hydroxycortisol by 11β-HSD type 1.6,7 Previous in vitro work has suggested that CYP3A4 in the liver is the main enzyme responsible for the 6β-hydroxylation of cortisol and cortisone making cortisol metabolism an attractive choice as an endogenous biomarker of CYP3A4 activity.6 This research investigated the effect of isotretinoin on CYP3A4 activity in severe acne patients using the 6β-hydroxylations of cortisol and cortisone as endogenous biomarkers. The plasma concentrations and renal clearance of cortisol, cortisone, 6β-hydroxycortisol, and 6β-hydroxycortisone are reported, along with the urinary and plasma metabolic ratios, and the apparent formation clearances of 6β- hydroxycortisol, and 6β-hydroxycortisone. The results show that there was an increase in the plasma concentrations of cortisol and 6β-hydroxycortisol suggesting that isotretinoin is impacting cortisol production. Furthermore, a decrease in 6β-hydroxycortisol renal clearance was found which supports isotretinoin impacting the interconversion of cortisol and cortisone in the kidney. Surprisingly, we saw a decrease in the formation clearance of 6β-hydroxycortisone which could imply CYP3A4 inhibition. Lastly, there was no change in plasma or urinary metabolic ratios which supports CYP3A4 not being induced by isotretinoin.application/pdfen-USnonePharmaceutical sciencesPharmaceuticsThesis