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Research ArticleArticle

Hepatoselective Nitric Oxide (NO) Donors, V-PYRRO/NO and V-PROLI/NO, in Nonalcoholic Fatty Liver Disease: A Comparison of Antisteatotic Effects with the Biotransformation and Pharmacokinetics

Kamil Kus, Maria Walczak, Edyta Maslak, Agnieszka Zakrzewska, Anna Gonciarz-Dytman, Piotr Zabielski, Barbara Sitek, Krystyna Wandzel, Agnieszka Kij, Adrian Chabowski, Ryan J. Holland, Joseph E. Saavedra, Larry K. Keefer and Stefan Chlopicki
Drug Metabolism and Disposition July 2015, 43 (7) 1028-1036; DOI: https://doi.org/10.1124/dmd.115.063388
Kamil Kus
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Maria Walczak
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Edyta Maslak
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Agnieszka Zakrzewska
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Anna Gonciarz-Dytman
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Piotr Zabielski
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Barbara Sitek
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Krystyna Wandzel
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Agnieszka Kij
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Adrian Chabowski
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Ryan J. Holland
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Joseph E. Saavedra
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Larry K. Keefer
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Stefan Chlopicki
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
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Abstract

V-PYRRO/NO [O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate] and V-PROLI/NO (O2-vinyl-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate), two structurally similar diazeniumdiolate derivatives, were designed as liver-selective prodrugs that are metabolized by cytochrome P450 isoenzymes, with subsequent release of nitric oxide (NO). Yet, their efficacy in the treatment of nonalcoholic fatty liver disease (NAFLD) and their comparative pharmacokinetic and metabolic profiles have not been characterized. The aim of the present work was to compare the effects of V-PYRRO/NO and V-PROLI/NO on liver steatosis, glucose tolerance, and liver fatty acid composition in C57BL/6J mice fed a high-fat diet, as well as to comprehensively characterize the ADME (absorption, distribution, metabolism and excretion) profiles of both NO donors. Despite their similar structure, V-PYRRO/NO and V-PROLI/NO showed differences in pharmacological efficacy in the murine model of NAFLD. V-PYRRO/NO, but not V-PROLI/NO, attenuated liver steatosis, improved glucose tolerance, and favorably modified fatty acid composition in the liver. Both compounds were characterized by rapid absorption following i.p. administration, rapid elimination from the body, and incomplete bioavailability. However, V-PYRRO/NO was eliminated mainly by the liver, whereas V-PROLI/NO was excreted mostly in unchanged form by the kidney. V-PYRRO/NO was metabolized by CYP2E1, CYP2C9, CYP1A2, and CYP3A4, whereas V-PROLI/NO was metabolized mainly by CYP1A2. Importantly, V-PYRRO/NO was a better NO releaser in vivo and in the isolated, perfused liver than V-PROLI/NO, an effect compatible with the superior antisteatotic activity of V-PYRRO/NO. In conclusion, V-PYRRO/NO displayed a pronounced antisteatotic effect associated with liver-targeted NO release, whereas V-PROLI/NO showed low effectiveness, was not taken up by the liver, and was eliminated mostly in unchanged form by the kidney.

Footnotes

    • Received January 17, 2015.
    • Accepted April 9, 2015.
  • This work was supported by the Polish National Science Center [DEC-2013/11/N/NZ7/00749] and the European Union from the resources of the European Regional Development Fund under the Innovative Economy Programme, grant coordinated by JCET-UJ [POIG.01.01.02-00-069/09].

  • dx.doi.org/10.1124/dmd.115.063388.

  • U.S. Government work not protected by U.S. copyright
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Drug Metabolism and Disposition: 43 (7)
Drug Metabolism and Disposition
Vol. 43, Issue 7
1 Jul 2015
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Research ArticleArticle

Effects of Two NO Donors on NAFLD and Their ADME Profiles

Kamil Kus, Maria Walczak, Edyta Maslak, Agnieszka Zakrzewska, Anna Gonciarz-Dytman, Piotr Zabielski, Barbara Sitek, Krystyna Wandzel, Agnieszka Kij, Adrian Chabowski, Ryan J. Holland, Joseph E. Saavedra, Larry K. Keefer and Stefan Chlopicki
Drug Metabolism and Disposition July 1, 2015, 43 (7) 1028-1036; DOI: https://doi.org/10.1124/dmd.115.063388

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Research ArticleArticle

Effects of Two NO Donors on NAFLD and Their ADME Profiles

Kamil Kus, Maria Walczak, Edyta Maslak, Agnieszka Zakrzewska, Anna Gonciarz-Dytman, Piotr Zabielski, Barbara Sitek, Krystyna Wandzel, Agnieszka Kij, Adrian Chabowski, Ryan J. Holland, Joseph E. Saavedra, Larry K. Keefer and Stefan Chlopicki
Drug Metabolism and Disposition July 1, 2015, 43 (7) 1028-1036; DOI: https://doi.org/10.1124/dmd.115.063388
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