This thesis delves into the realm of ADMET research, with a specific focus on the metabolic profile of the well-known drug propranolol. Despite its age, propranolol has garnered renewed interest due to new applications, prompting investigations into its metabolism and phase I metabolites, 4-, 5-, and 7-hydroxypropranolol. The study employs comprehensive reaction phenotyping to explore the glucuronidation of propranolol and its hydroxypropranolol metabolites, uncovering stereoselectivity patterns among UGT1 and UGT2 enzymes. Regioselective glucuronidation studies highlight a preference for aromatic-linked glucuronidation in vivo, though in vitro conditions reveal potential for aliphatic-linked glucuronidation. The glucosidation of propranolol is also explored, with UGTs exhibiting activity in this alternative metabolic pathway. Additionally, the thesis investigates the mutual modulation between CYP and UGT enzymes during propranolol metabolism, revealing a significant enhancement of CYP2D6 activity by UGT1A7, UGT1A8, and UGT1A9, while UGT2A1 has no influence. Conversely, CYP2D6 suppresses the glucuronidation process catalyzed by the four UGTs. Notably, this study unveils a functional interaction between CYP2D6 and UGT1A subfamilies in drug metabolism, providing valuable insights into the intricate interplay of enzymes involved in propranolol's metabolic pathways.
