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Determination of the P450‐ and UGT‐dependent Biotransformation of the Anti‐HIV Drugs Cabotegravir and Dolutegravir
Author(s) -
Madeen Erin,
Bumpus Namandjé
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.822.14
Subject(s) - metabolite , chemistry , dolutegravir , microsome , glucuronidation , cyp3a4 , glucuronide , pharmacology , pharmacokinetics , cytochrome p450 , glucuronosyltransferase , biochemistry , metabolism , enzyme , human immunodeficiency virus (hiv) , biology , viral load , antiretroviral therapy , immunology
Cabotegravir (CAB) and Dolutegravir (DTG) are FDA approved viral integrase strand transfer inhibitors in oral formulation as antiretroviral therapeutics, while CAB is additionally in clinical trials as pre‐exposure prophylaxis (PrEP) for the prevention of HIV transmission. The molecular structure of CAB and DTG are remarkably similar, only differing in the terminal ring, a pentane ring on CAB and a hexane ring on DTG. The impact of structure on the metabolism of CAB and DTG were investigated. In order to investigate CAB and DTG metabolite formation human liver microsomes (HLM), c‐DNA expressed cytochrome P450 isozymes (P450s: 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5), or c‐DNA expressed UDP‐glucuronosyltransferase (UGT) isozymes (UGTs 1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B15, 2B17) were employed. Separation, detection and identification were performed using UPLC‐MS/MS. HLM incubation resulted in the formation of two mono‐oxygenated metabolites of each CAB and DTG. The P450s that produced the greatest abundance of the CAB mono‐oxygenated metabolite M1 were P450s 2D6, 3A4, and 3A5, while DTG mono‐oxygenated metabolite M1 was produced by P450s 2B6, 2D6, 3A4, and 3A5. The P450 that produced the greatest abundance of mono‐oxygenated CAB metabolite M2 was CYP3A4 while DTG M2 was produced by P450s 1A2 and 3A4. Both CAB and DTG were directly glucuronidated in HLM incubations. The primary UGTs responsible for CAB direct conjugation were found to be UGT1A1, 1A3, and 1A9. In addition, a mono‐oxy‐CAB‐glucuronide conjugate was detected and formed by UGT2B7, while no glucuronide conjugate species of mono‐oxy‐DTG were detected. These data suggest that, despite the similarity of the molecular structure of these compounds, there are differing routes of P450 and UGT mediated metabolism. Support or Funding Information R01 GM103853