Uridine 5’-diphosphate (UDP)-glucuronosyl transferases (UGTs) are important drug-metabolizing enzymes, which contribute to the elimination of numerous marketed drugs that contain alcohol, phenol, amine or carboxylic acid functionalities. Currently, 19 UGT proteins have been identified in humans, which are dived into three subfamilies–UGT1A, 2A, and 2B. UGT mRNAs have been detected in various tissues, with particularly abundant expression in the liver and intestine. Because UGTs are also located in the small intestine (similar to the presence of oxidative enzymes such as cytochrome P4503A4), there is a general concern that intestinal glucuronidation will have a pronounced effect on oral bioavailability (F). For example, the extremely low oral F (~ 2%) of raloxifene in humans has been attributed to significant intestinal first-pass glucuronidation. With the increasing awareness of the importance of intestinal first-pass metabolism by P4503A4 and UGTs in humans, in vitro and in vivo studies in animals and humans are considered important in projecting human oral absorption for investigational drug candidates. Limited information is available, however, on the intestinal glucuronidation capacity (including mRNA expression of relevant UGT isoforms and species differences in glucuronidation) in animals relative to humans. This presentation will highlight tactics deployed in studying intestinal glucuronidation in a preclinical discovery setting using in vitro reagents and animal pharmacokinetics studies. Using literature examples and a recent case study with an AMP kinase activator PF-06409577, data will be presented to demonstrate the perils in extrapolating animal oral F to humans without a thorough mechanistic understanding of species differences in intestinal glucuronidation including the role of tissue-specific UGT isoforms.

First-pass intestinal glucuronidation as a potential obstacle for oral absorption of small molecule drug candidates: When should we worry?

253rd National Meeting (2017)

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