LEVERAGING DRUG METABOLISM AND DRUG-DRUG INTERACTION MECHANISMS OF 17β-HYDROXY STEROIDS FOR DRUG DISCOVERY AND PERCISON MEDICINE

Namrata Keshav Bachhav

doi:10.7273/000007910

UDP-Glucuronyltransferase 2B17 (UGT2B17) is a highly polymorphic drug metabolizing enzyme with high inter-individual variability in its expression and activity, which critically determines the pharmacokinetics (PK) and pharmacodynamics (PD) of several clinically important orally administered drugs. Higher abundance of UGT2B17 in the intestine compared to the liver leads to substantial intestinal first-pass metabolism, resulting in poor drug bioavailability and greater variation in drug responses among different individuals. Both genetic as well as non-genetic factors, such as copy number variation, single-nucleotide polymorphism, sex, race, and age contribute to the high (>3000-fold) variability in UGT2B17 expression and activity. This dissertation focuses on the role of UGT2B17 in metabolism and drug-drug interactions of 17β-hydroxy steroids (17β-OH steroids), highlighting potential applications in precision medicine. Chapter 1 compiled the clinical impact of UGT2B17 on the metabolism of a few key drugs such as MK7246, diclofenac, testosterone, belzutifan, losartan, and associated challenges. Experimental methodologies such as in vitro, in silico, and in vivo studies used for examining the activity of UGT2B17 are also discussed. Chapter 2 focusses on a mechanistic study involving UGT2B17 mediated metabolism of an investigational 17β-OH steroidal drug, 11β-Methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC), a prodrug of 11β-MNT, which is under development as a male oral contraceptive. In vitro experiments using cryopreserved human hepatocytes and intestinal fractions established 11β-MNT glucuronide (11β-MNTG) as a major biotransformation product and the reaction phenotyping established UGT2B17 as a key enzyme mediating this reaction. Chapter 3 includes an investigation on another important 17β-OH steroid, oral testosterone undecanoate (TU), which is clinically important for hypogonadism therapy. This chapter demonstrated that curcumin can increase systemic bioavailability of testosterone after co-administration of curcumin with oral TU, which was evident by significant increases in the plasma concentration-time area under the curve (AUC1-6 hr) and the peak plasma concentration (Cmax) for testosterone by 50% and 80%, respectively. Chapter 4 delves into a new metabolomics-based drug metabolizing enzymes and transporters (DMET) biomarker discovery (MDBD) approach of finding endogenous UGT substrates leveraging pooled human urine. A curated database of potential endogenous glucuronides (EGs) and mass spectrometry analysis revealed 15 endogenous UGT substrates. These substrates can be used as biomarkers for predicting drug-drug interactions and inter-individual differences. In summary, by understanding the drug metabolism and drug-drug interaction mechanisms of 17β-OH steroidal drugs, the dissertation proposes a potential therapeutic solution to improve bioavailability of these compounds. Further, the use of potential UGT biomarkers identified in this study can be leveraged for predicting UGT-mediated inter-individual variability and drug-drug interactions.

LEVERAGING DRUG METABOLISM AND DRUG-DRUG INTERACTION MECHANISMS OF 17β-HYDROXY STEROIDS FOR DRUG DISCOVERY AND PERCISON MEDICINE

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