title: 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.
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.
authors: 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.).
authors: Kamil
authors: K
authors: Kus
authors: 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.).
authors: Maria
authors: M
authors: Walczak
authors: 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.).
authors: Edyta
authors: E
authors: Maslak
authors: 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.).
authors: Agnieszka
authors: A
authors: Zakrzewska
authors: 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.).
authors: Anna
authors: A
authors: Gonciarz-Dytman
authors: 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.).
authors: Piotr
authors: P
authors: Zabielski
authors: 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.).
authors: Barbara
authors: B
authors: Sitek
authors: 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.).
authors: Krystyna
authors: K
authors: Wandzel
authors: 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.).
authors: Agnieszka
authors: A
authors: Kij
authors: 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.).
authors: Adrian
authors: A
authors: Chabowski
authors: 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.).
authors: Ryan J
authors: RJ
authors: Holland
authors: 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.).
authors: Joseph E
authors: JE
authors: Saavedra
authors: 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.).
authors: Larry K
authors: LK
authors: Keefer
authors: 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.) stefan.chlopicki@jcet.eu.
authors: Stefan
authors: S
authors: Chlopicki
mesh_terms: D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000378:metabolism; D018149:Glucose Intolerance; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy*; D011759:Pyrrolidines / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014226:Triazenes / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D005227:Fatty Acids; D020030:Nitric Oxide Donors; C107010:O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; C560906:O2-vinyl 1-(2-(carboxylato)pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; D011759:Pyrrolidines; D014226:Triazenes; D003577:Cytochrome P-450 Enzyme System