title: Differential effects of liver steatosis on pharmacokinetic profile of two closely related hepatoselective NO-donors; V-PYRRO/NO and V-PROLI/NO.
abstract: OBJECTIVE
  To analyze the effect of liver steatosis and obesity on pharmacokinetic profile of two structurally-related liver-selective NO-donors - V-PYRRO/NO and V-PROLI/NO.
  
  
  METHODS
  C57BL/6 mice were fed control or high-fat diet for 15 weeks to induced liver steatosis and obesity (HFD mice). Pharmacokinetics and renal elimination studies were conducted in vivo following iv dosing of V-PYRRO/NO and V-PROLI/NO (0.03mmol/kg). Hepatic clearance was evaluated ex vivo in the isolated perfused mice liver and in vitro with the use of liver microsomes.
  
  
  RESULTS
  V-PYRRO/NO and V-PROLI/NO, despite similar structure, displayed different pharmacokinetic properties. V-PYRRO/NO was uptaken and metabolized by the liver, while V-PROLI/NO was eliminated unchanged with urine. In HFD mice, despite increased CYP450 metabolism of V-PYRRO/NO the elimination rate was slower most likely due to the impairment of hepatic microcirculation caused by liver fat accumulation. In turn, in HFD mice renal clearence of V-PROLI/NO was accelerated and volume of distribution was increased most likely due to additional intracellular water in HFD mice.
  
  
  CONCLUSIONS
  The pharmacokinetics of V-PROLI/NO, the novel proline-based analog of V-PYRRO/NO with additional single carboxylic acid moiety, attached to the molecule of V-PYRRO/NO to improve the water solubility, was differently affected by liver steatosis and obesity as compared with the parent compound V-PYRRO/NO.
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kus
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland.
authors.forename: Edyta
authors.initials: E
authors.lastname: Kus
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zakrzewska
authors.affiliation: Departament of Pharmaceutical Biophysics, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Jawien
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sitek
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland; Chair and Department of Toxicology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Walczak
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland; Chair of Pharmacology, Jagiellonian University Medical College, Kraków, Poland. Electronic address: stefan.chlopicki@jcet.eu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Chlopicki
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D008862:Microsomes, Liver / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000493:pharmacokinetics*; D009765:Obesity / Q000150:complications*; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D014018:Tissue Distribution; D014226:Triazenes / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: 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
keywords: Liver steatosis; Liver-targeted prodrugs; Pharmacokinetics; Therapeutic efficacy