Examining Physiologically Based Pharmacokinetic Model Assumptions for Cross-Tissue Similarity of Activity per Unit of Enzyme: The Case Example of Uridine 50-Diphosphate Glucuronosyltransferase

Abstract

The default assumption during in vitro in vivo extrapolation (IVIVE) to predict metabolic clearance in physiologically based pharmacokinetics (PBPK) is that protein expression and activity have the same relationship in various tissues. This assumption is examined for uridine 50-diphosphate glucuronosyltransferases (UGTs), a case example where expression and hence metabolic activity are distributed across various tissues. Our literature analysis presents overwhelming evidence of a greater UGT activity per unit of enzyme (higher kcat) in kidney and intestinal tissues relative to liver (greater than 200-fold for UGT2B7). This analysis is based on application of abundance values reported using similar proteomic techniques and within the same laboratory. Our findings call into question the practice of assuming similar kcat during IVIVE estimations as part of PBPK and call for a systematic assessment of the kcat of various enzymes across different organs. The analysis focused on compiling data for probe substrates that were common for two or more of the studied tissues to allow for reliable comparison of cross-tissue enzyme kinetics; this meant that UGT enzymes included in the study were limited to UGT1A1, 1A3, 1A6, 1A9, and 2B7. Significantly, UGT1A9 (n = 24) and the liver (n = 27) were each found to account for around half of the total dataset; these were found to correlate with hepatic UGT1A9 data found in 15 of the studies, highlighting the need for more research into extrahepatic tissues and other UGT isoforms.