Mechanistic Assessment of Extrahepatic Contributions to Glucuronidation of Integrase Strand Transfer Inhibitors

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Stephanie N LiuBrandon T Gufford

Abstract

Integrase strand transfer inhibitor (INSTI)-based regimens dominate initial human immunodeficiency virus treatment. Most INSTIs are metabolized predominantly via UDP-glucuronosyltransferases (UGTs). For drugs predominantly metabolized by UGTs, including INSTIs, in vitro data recovered from human liver 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), intestine (HIMs), and kidney (HKMs) tissues; human embryonic kidney 293 cells expressing individual UGTs; and recombinant UGTs. 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 renal UGT1A9 (dolutegra...Continue Reading

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Citations

Sep 3, 2020·The AAPS Journal·Sana-Kay Whyte-Allman, Reina Bendayan
Sep 7, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jim ZhengRaju Subramanian
Feb 23, 2021·ACS Pharmacology & Translational Science·Herana Kamal SeneviratneNamandjé N Bumpus

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