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Research ArticleMetabolism, Transport, and Pharmacogenomics

ABCG2 Deficiency Does Not Alter Dolutegravir Metabolism and Pharmacokinetics

Junjie Zhu, Xin Tian, Amina I. Shehu, Deborah K. McMahon and Xiaochao Ma
Journal of Pharmacology and Experimental Therapeutics July 2020, 374 (1) 38-43; DOI: https://doi.org/10.1124/jpet.119.264424
Junjie Zhu
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy (J.Z., X.T., A.I.S., X.M.) and Division of Infectious Disease, Department of Medicine (D.K.M.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Xin Tian
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy (J.Z., X.T., A.I.S., X.M.) and Division of Infectious Disease, Department of Medicine (D.K.M.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Amina I. Shehu
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy (J.Z., X.T., A.I.S., X.M.) and Division of Infectious Disease, Department of Medicine (D.K.M.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Deborah K. McMahon
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy (J.Z., X.T., A.I.S., X.M.) and Division of Infectious Disease, Department of Medicine (D.K.M.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Xiaochao Ma
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy (J.Z., X.T., A.I.S., X.M.) and Division of Infectious Disease, Department of Medicine (D.K.M.), University of Pittsburgh, Pittsburgh, Pennsylvania
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    Fig. 1.

    DTG metabolism and disposition in hepatocytes. M1, M2, M3, M4, and M5 are the metabolites of DTG. M2 and M3 are formed by UGT1A1 and CYP3A4, respectively. ABCG2 and ABCB1 are the potential transporters mediating the efflux of DTG from hepatocytes to the biliary system. The current work investigated the impact of ABCG2 deficiency on DTG metabolism and pharmacokinetics in mice.

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    Fig. 2.

    Systemic pharmacokinetics of DTG in WT and Abcg2-null mice. (A and B) Genetic and functional validation of Abcg2-null mice. PPIX was used as a substrate of ABCG2. (C) Serum concentration-time curves of DTG in WT and Abcg2-null mice. The mice were administrated with a single dose of DTG (20 mg/kg, p.o.). (D–G) Comparison of major pharmacokinetic parameters of DTG between WT and Abcg2-null mice. PPIX and DTG were measured by UPLC-QTOFMS. Pharmacokinetic parameters were calculated by noncompartmental model analysis on Phoenix WinNonlin. All data are expressed as means ± S.D. (n = 4). ***P < 0.001 vs. WT. CL, clearance; t1/2, elimination half-life; VZ, volume of distribution.

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    Fig. 3.

    Tissue-specific pharmacokinetics of DTG in WT and Abcg2-null mice. The mice were administrated with a single dose of DTG (20 mg/kg, p.o.). (A, C, and E) Concentration-time curves of DTG in the liver, kidney, and brain of WT and Abcg2-null mice. (B, D, and F) AUCs of DTG in the liver, kidney, and brain of WT and Abcg2-null mice. AUCs were calculated by Graphpad Prism. All data are expressed as means ± S.D. (n = 4). N.D., not detected.

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    Fig. 4.

    Excretion of DTG and its metabolites in feces and urine of WT and Abcg2-null mice. Feces and urine were collected overnight from mice treated with a single dose of DTG. (A and B) The abundance of DTG in feces and urine. (C–F) Comparison of DTG and its metabolites in feces and urine. (G and H) Comparison of DTG metabolites between WT and Abcg2-null mice. N.D., not detected. The data (A, B, G, and H) are expressed as means ± S.D. (n = 4).

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Journal of Pharmacology and Experimental Therapeutics: 374 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 374, Issue 1
1 Jul 2020
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Research ArticleMetabolism, Transport, and Pharmacogenomics

ABCG2 Status and Dose Adjustment of Dolutegravir

Junjie Zhu, Xin Tian, Amina I. Shehu, Deborah K. McMahon and Xiaochao Ma
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 38-43; DOI: https://doi.org/10.1124/jpet.119.264424

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Research ArticleMetabolism, Transport, and Pharmacogenomics

ABCG2 Status and Dose Adjustment of Dolutegravir

Junjie Zhu, Xin Tian, Amina I. Shehu, Deborah K. McMahon and Xiaochao Ma
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 38-43; DOI: https://doi.org/10.1124/jpet.119.264424
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