%0 Journal Article %A Stephanie N Liu %A Jessica Bo Li Lu %A Christy JW Watson %A Philip Lazarus %A Zeruesenay Desta %A Brandon T Gufford %T Mechanistic Assessment of Extrahepatic Contributions to Glucuronidation of Integrase Strand Transfer Inhibitors %D 2019 %R 10.1124/dmd.118.085035 %J Drug Metabolism and Disposition %P dmd.118.085035 %X Integrase strand transfer inhibitor (INSTI)-based regimens dominate initial HIV treatment. Most INSTIs are metabolized predominantly via UDP-glucuronosyltransferases (UGTs). For drugs predominantly metabolized by UGTs, including INSTIs, in vitro data recovered from human hepatic microsomes (HLMs) alone often underpredict human oral clearance. While several factors may contribute, extrahepatic glucuronidation may contribute to this underprediction. Thus, we comprehensively characterized the kinetics for the glucuronidation of INSTIs (cabotegravir, dolutegravir, and raltegravir) using: pooled human microsomal preparations from liver (HLMs), intestinal (HIMs) and kidney (HKMs) tissues; HEK293 cells expressing individual UGTs; and recombinant UGTs (rUGTs). In vitro glucuronidation of cabotegravir (HLMs≈HKMs>>>HIMs), dolutegravir (HLMs>HIMs>>HKMs) and raltegravir (HLMs>HKMs>> HIMs) occurred in hepatic and extrahepatic tissues. The kinetic data from expression systems suggested the major enzymes in each tissue: hepatic UGT1A9>UGT1A1 (dolutegravir and raltegravir) and UGT1A1 (cabotegravir); intestinal UGT1A3>UGT1A8>UGT1A1 (dolutegravir) and UGT1A8>UGT1A1 (raltegravir); and kidney UGT1A9 (dolutegravir and raltegravir). Enzymes catalyzing cabotegravir glucuronidation in the kidney and intestine could not be identified unequivocally. Using data from dolutegravir glucuronidation as a prototype, a "bottom-up" physiologically based pharmacokinetic (PBPK) model was developed in a stepwise approach and predicted dolutegravir oral clearance within 4.5-fold (hepatic data only), 2-fold (hepatic and intestinal data), and 32% (hepatic, intestinal, and renal data). These results suggest clinically meaningful glucuronidation of dolutegravir in tissues other than the liver. Incorporation of additional novel mechanistic and physiologic underpinnings of dolutegravir metabolism along with in silico approaches appear to be a powerful tool to accurately predict the clearance of dolutegravir from in vitro data. %U https://dmd.aspetjournals.org/content/dmd/early/2019/02/25/dmd.118.085035.full.pdf