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 5'-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 k_cat) 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 k_cat during IVIVE estimations as part of PBPK, and call for a systematic assessment of the k_cat 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.

Significance Statement During PBPK modelling (in vitro in vivo extrapolation) of drug clearance, the default assumption is that the activity per unit of enzyme (k_cat) is the same in all tissues. The analysis provides preliminary evidence that this may not be the case, and that renal and intestinal tissues may have almost 250-fold greater UGT activity per unit of enzyme than liver tissues.