Mechanistic assessment of extrahepatic contributions to glucuronidation of integrase strand transfer inhibitors

Stephanie N. Liu, Jessica Bo Li Lu, Christy J.W. Watson, Philip Lazarus, Zeruesenay Desta, Brandon T. Gufford

Research output: Contribution to journalArticle

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 (HLMsHKMs&&&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 (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 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 appears to be a powerful tool to accurately predict the clearance of dolutegravir from in vitro data.

Original languageEnglish (US)
Pages (from-to)535-544
Number of pages10
JournalDrug Metabolism and Disposition
Volume47
Issue number5
DOIs
StatePublished - May 1 2019

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Integrases
Glucuronosyltransferase
Liver Microsomes
Liver
Kidney
Intestines
dolutegravir
Enzymes
Information Systems
Computer Simulation
Pharmacokinetics
Raltegravir Potassium
HIV

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Mechanistic assessment of extrahepatic contributions to glucuronidation of integrase strand transfer inhibitors. / Liu, Stephanie N.; Lu, Jessica Bo Li; Watson, Christy J.W.; Lazarus, Philip; Desta, Zeruesenay; Gufford, Brandon T.

In: Drug Metabolism and Disposition, Vol. 47, No. 5, 01.05.2019, p. 535-544.

Research output: Contribution to journalArticle

Liu, Stephanie N. ; Lu, Jessica Bo Li ; Watson, Christy J.W. ; Lazarus, Philip ; Desta, Zeruesenay ; Gufford, Brandon T. / Mechanistic assessment of extrahepatic contributions to glucuronidation of integrase strand transfer inhibitors. In: Drug Metabolism and Disposition. 2019 ; Vol. 47, No. 5. pp. 535-544.
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