CYP1A1 and 1B1-mediated metabolic pathways of dolutegravir, an HIV integrase inhibitor
| Autor: | Deborah McMahon, Pengcheng Wang, Xiaochao Ma, Junjie Zhu, Jie Lu, Feng Li, Amina I. Shehu, Wen Xie |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pharmacology chemistry.chemical_classification biology CYP1B1 Metabolite 030106 microbiology Cytochrome P450 Integrase inhibitor respiratory system Biochemistry Integrase 03 medical and health sciences Metabolic pathway chemistry.chemical_compound Enzyme chemistry Dolutegravir biology.protein heterocyclic compounds |
| Zdroj: | Biochemical Pharmacology. 158:174-184 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2018.10.012 |
| Popis: | Dolutegravir (DTG), a potent integrase inhibitor, is part of a recommended initial regimen for the treatment of human immunodeficiency virus (HIV). Prior reports demonstrated that the clearance of DTG was higher in current smokers than non-smokers, but the mechanism remains unclear. Using a metabolomic approach, M4 (an aldehyde) was identified as a novel metabolite of DTG. In addition, the formation of M4 was found to be mediated by cytochrome P450 (CYP) 1A1 and 1B1, the enzymes that can be highly induced by cigarette smoking. CYP1A1 and 1B1 were also identified as the major enzymes contributing to the formation of M1 (an N-dealkylated metabolite of DTG) and M5 (an aldehyde). Furthermore, the production of M1 and M4 was significantly increased in the lung of mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin, an inducer of CYP1A1 and 1B1. In summary, the current study uncovered the CYP1A1 and 1B1-mediated metabolic pathways of DTG. These data suggest that persons with HIV infection receiving DTG should be cautious to cigarettes, and drugs, or exposure to environmental chemicals that induce CYP1A1 and 1B1. |
| Databáze: | OpenAIRE |
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