Metabolism, Excretion, and Mass Balance of the HIV-1 Integrase Inhibitor Dolutegravir in Humans

被引:117
|
作者
Castellino, Stephen [1 ]
Moss, Lee [1 ]
Wagner, David [1 ]
Borland, Julie [1 ]
Song, Ivy [1 ]
Chen, Shuguang [1 ]
Lou, Yu [1 ]
Min, Sherene S. [1 ]
Goljer, Igor [2 ]
Culp, Amanda [1 ]
Piscitelli, Stephen C. [1 ]
Savina, Paul M. [1 ]
机构
[1] GlaxoSmithKline, Res Triangle Pk, NC USA
[2] GlaxoSmithKline, King Of Prussia, PA USA
关键词
IN-VITRO; STRAND TRANSFER; IDENTIFICATION; S/GSK1349572; MECHANISMS; SAFETY; ADULTS;
D O I
10.1128/AAC.00292-13
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [C-14] dolutegravir at a dose of 20 mg (80 mu Ci). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives (t(1/2)) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.
引用
收藏
页码:3536 / 3546
页数:11
相关论文
共 50 条
  • [1] The comparative disposition and metabolism of dolutegravir, a potent HIV-1 integrase inhibitor, in mice, rats, and monkeys
    Moss, Lee
    Wagner, David
    Kanaoka, Eri
    Olson, Katie
    Yueh, Yun Lan
    Bowers, Gary D.
    XENOBIOTICA, 2015, 45 (01) : 60 - 70
  • [2] New integrase inhibitor dolutegravir approved by US FDA for HIV-1 treatment
    McCarthy, Jacob
    FUTURE MICROBIOLOGY, 2013, 8 (10) : 1242 - 1243
  • [3] New integrase inhibitor dolutegravir approved by US FDA for HIV-1 treatment
    McCarthy, Jacob
    FUTURE VIROLOGY, 2013, 8 (10) : 945 - 946
  • [4] Dolutegravir, a Second-Generation Integrase Inhibitor for the Treatment of HIV-1 Infection
    Rathbun, R. Chris
    Lockhart, Staci M.
    Miller, Misty M.
    Liedtke, Michelle D.
    ANNALS OF PHARMACOTHERAPY, 2014, 48 (03) : 395 - 403
  • [5] Synthesis of Three Key Impurities of Drug Dolutegravir: An Inhibitor of HIV-1 Integrase
    Garrepalli, Sailaja
    Gudipati, Ramesh
    Ravindhranath, Kunta
    Pal, Manojit
    POLYCYCLIC AROMATIC COMPOUNDS, 2023, 43 (04) : 3706 - 3719
  • [6] HIV-1 integrase inhibitor
    Lloyd, AW
    DRUG DISCOVERY TODAY, 1996, 1 (04) : 170 - 170
  • [7] Raltegravir: an integrase inhibitor for HIV-1
    Evering, Teresa H.
    Markowitz, Martin
    EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2008, 17 (03) : 413 - 422
  • [8] Metabolism, Excretion, and Mass Balance of Solithromycin in Humans
    MacLauchlin, Christopher
    Schneider, Stephen E.
    Keedy, Kara
    Fernandes, Prabhavathi
    Jamieson, Brian D.
    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2018, 62 (05)
  • [9] DOLUTEGRAVIR HIV Integrase Inhibitor Treatment of HIV Infection
    Wainberg, Mark A.
    Quashie, Peter K.
    Mesplede, Thibault
    DRUGS OF THE FUTURE, 2012, 37 (10) : 697 - 707
  • [10] DOLUTEGRAVIR, AN HIV INTEGRASE INHIBITOR FOR THE TREATMENT OF HIV INFECTION
    Temesgen, Z.
    Talwani, R.
    Rizza, S. A.
    DRUGS OF TODAY, 2014, 50 (01) : 7 - 14