Evidence map›Paper›PMID 25870102›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2015

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 and 4 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Drug metabolism and disposition: the biological fate of chemicals, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
0.9field-weighted citation impact, top 25% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed, 19 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 5 institutions in 2 countries.

Kamil KusJagiellonian 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.).
Maria WalczakJagiellonian 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.).
Edyta MaslakJagiellonian 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.).
Agnieszka ZakrzewskaJagiellonian 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.).
Anna Gonciarz-DytmanJagiellonian 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.).
Piotr ZabielskiJagiellonian 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.).
Barbara SitekJagiellonian 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.).
Krystyna WandzelJagiellonian 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.).
Agnieszka KijJagiellonian 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.).
Adrian ChabowskiJagiellonian 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.).
Ryan J HollandJagiellonian 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.).
Joseph E SaavedraJagiellonian 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.).
Larry K KeeferJagiellonian 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 ChlopickiJagiellonian 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.
Jagiellonian University · PLMedical University of Białystok · PLFrederick National Laboratory for Cancer Research · USNational Cancer Institute · USLeidos (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

AnimalsBiotransformationCytochrome P-450 Enzyme SystemDiet, High-FatFatty AcidsGlucose IntoleranceIntestinal AbsorptionKidneyLiverMaleMiceMice, Inbred C57BLNitric Oxide DonorsNon-alcoholic Fatty Liver DiseasePyrrolidinesRatsCytochrome P-450 Enzyme SystemFatty AcidsNitric Oxide DonorsO2-vinyl 1-(2-(carboxylato)pyrrolidin-1-yl)diazen-1-ium-1,2-diolateO(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolatePyrrolidinesTriazenes

Identifiers

PMID25870102
PMCPMC11024901
OpenAlexW2165987401

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.