Metabolism and Pathways for Denitration of Organic Nitrates in the Human Liver

Liver first-pass metabolism differs considerably among organic nitrates, but little information exists on the mechanism of denitration of these compounds in hepatic tissue. The metabolism of nitrooxybutyl-esters of flurbiprofen and ferulic-acid, a class of organic nitrates with potential therapeutic implication in variety of different conditions, was investigated in comparison with glyceryl trinitrate (GTN) in human liver by a multiple approach, using a spontaneous metabolism-independent nitric oxide (NO) donor [3-(aminopropyl)-1-hydroxy-3-isopropyl-2-oxo-1-triazene (NOC-5)] as a reference tool. Nitrooxybutyl-esters were rapidly and quantitatively metabolized to their respective parent compounds and the organic nitrate moiety nitrooxybutyl-alcohol (NOBA). Differently from GTN, which was rapidly and completely metabolized to nitrite, NOBA was slowly metabolized to nitrate. In contrast to the spontaneous NO donor NOC-5, NOBA and GTN did not generate detectable NO and failed to suppress the activity of cytochrome P450, an enzyme known to be inhibited by NO. The direct identification of NOBA after liver metabolism targets this compound as the functional organic nitrate metabolite of nitrooxybutyl-esters. Moreover, the investigation of the pathways for denitration of NOBA and GTN suggests that organic nitrates are not primarily metabolized to NO in the liver but to different extents of nitrite or nitrate depending in their different chemical structure. Therefore, cytochrome P450-dependent metabolism of concomitant drugs is not likely to be affected by oral coadministration of organic nitrates. However, the first pass may differently affect the pharmacological profile of organic nitrates in connection with the different extent of denitration and the distinct bioactive species generated and exported from the liver (nitrate or nitrite).

[1]  W. Murrell.  Nitro-Glycerine as a Remedy for Angina Pectoris , 2010 .

[2]  N. Pitsikas,et al.  The nitric oxide-releasing derivative of ferulic acid NCX 2057 antagonized delay-dependent and scopolamine-induced performance deficits in a recognition memory task in the rat , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[3]  M. Gladwin,et al.  Nitrate and nitrite in biology, nutrition and therapeutics. , 2009, Nature chemical biology.

[4]  J. F. Herrero,et al.  NCX 2057, a novel NO‐releasing derivative of ferulic acid, suppresses inflammatory and nociceptive responses in in vitro and in vivo models , 2009, British journal of pharmacology.

[5]  S. Dahlén,et al.  Specific mediator inhibition by the NO donors SNP and NCX 2057 in the peripheral lung: implications for allergen-induced bronchoconstriction , 2009, Respiratory research.

[6]  T. Münzel,et al.  Mitochondrial aldehyde dehydrogenase (ALDH-2)--maker of and marker for nitrate tolerance in response to nitroglycerin treatment. , 2009, Chemico-biological interactions.

[7]  Mark T. Gladwin,et al.  The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics , 2008, Nature Reviews Drug Discovery.

[8]  A. Monopoli,et al.  A new class of nitric oxide‐releasing derivatives of cetirizine; pharmacological profile in vascular and airway smooth muscle preparations , 2007, British journal of pharmacology.

[9]  P. Tocchetti,et al.  In Vitro Metabolism of (Nitrooxy)butyl Ester Nitric Oxide-Releasing Compounds: Comparison with Glyceryl Trinitrate , 2006, Journal of Pharmacology and Experimental Therapeutics.

[10]  U. Fagerholm,et al.  Clinical pharmacokinetics of the cyclooxygenase inhibiting nitric oxide donator (CINOD) AZD3582 , 2005 .

[11]  T. Münzel,et al.  Explaining the phenomenon of nitrate tolerance. , 2005, Circulation research.

[12]  E. Ongini,et al.  Activity of flurbiprofen and chemically related anti-inflammatory drugs in models of Alzheimer's disease , 2005, Brain Research Reviews.

[13]  S. Ralston,et al.  The flurbiprofen derivatives HCT1026 and HCT1027 inhibit bone resorption by a mechanism independent of COX inhibition and nitric oxide production. , 2004, Bone.

[14]  M. Giovannini,et al.  Comparison between Flurbiprofen and its Nitric Oxide-Releasing Derivatives HCT-1026 and NCX-2216 on Aβ(1-42)-Induced Brain Inflammation and Neuronal Damage in the Rat , 2004, International journal of immunopathology and pharmacology.

[15]  J. Lundberg,et al.  Inorganic nitrate is a possible source for systemic generation of nitric oxide. , 2004, Free radical biology & medicine.

[16]  E. Ongini,et al.  Attenuation of chronic neuroinflammation by a nitric oxide‐releasing derivative of the antioxidant ferulic acid , 2004, Journal of neurochemistry.

[17]  T. Münzel,et al.  Does Nitric Oxide Mediate the Vasodilator Activity of Nitroglycerin? , 2003, Circulation research.

[18]  A. Kozlov,et al.  Various intracellular compartments cooperate in the release of nitric oxide from glycerol trinitrate in liver , 2003, British journal of pharmacology.

[19]  S. Mnaimneh,et al.  Concomitant S‐, N‐, and heme‐nitros(yl)ation in biological tissues and fluids: implications for the fate of NO in vivo , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  G. Wenk,et al.  A nitric oxide-donating flurbiprofen derivative reduces neuroinflammation without interacting with galantamine in the rat. , 2002, European journal of pharmacology.

[21]  P. K. Moore,et al.  Pharmacology and potential therapeutic applications of nitric oxide‐releasing non‐steroidal anti‐inflammatory and related nitric oxide‐donating drugs , 2002, British journal of pharmacology.

[22]  J. Loscalzo,et al.  Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview. , 2002, Circulation research.

[23]  L. Keefer,et al.  Diazeniumdiolates: pro- and antioxidant applications of the "NONOates". , 2000, Free radical biology & medicine.

[24]  J. Parker,et al.  Nitrate therapy for stable angina pectoris. , 1999, The New England journal of medicine.

[25]  T. Nabeshima,et al.  Simultaneous Measurement of Nitrite and Nitrate Levels as Indices of Nitric Oxide Release in the Cerebellum of Conscious Rats , 1997, Journal of neurochemistry.

[26]  R. Busse,et al.  Specificity of different organic nitrates to elicit NO formation in rabbit vascular tissues and organs in vivo , 1995, British journal of pharmacology.

[27]  J. Siewert,et al.  Inhibition of cytochromes P4501A by nitric oxide. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[28]  J. Vane,et al.  Nitric oxide is a mediator of the decrease in cytochrome P450-dependent metabolism caused by immunostimulants. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[29]  U. Abshagen.  Pharmacokinetics of isosorbide mononitrate. , 1992, The American journal of cardiology.

[30]  M. Delaforge,et al.  Nitric oxide formation during microsomal hepatic denitration of glyceryl trinitrate: involvement of cytochrome P-450. , 1989, Biochemical and biophysical research communications.

[31]  L. Benet,et al.  Pharmacokinetics of nitroglycerin and metabolites in humans following oral dosing , 1988, Biopharmaceutics & drug disposition.

[32]  P. Needleman,et al.  Organic nitrates: relationship between biotransformation and rational angina pectoris therapy. , 1972, The Journal of pharmacology and experimental therapeutics.

[33]  B. Cuparencu,et al.  Nitrate esters of steroid hormones and related compounds. Preparation and biological properties. , 1969, Arzneimittel-Forschung.

[34]  W. Moss.  CASE OF SPONTANEOUS EVOLUTION. , 1831 .

[35]  Roberto Scatena.  Nitroflurbiprofen (NicOx). , 2004, Current opinion in investigational drugs.

[36]  D. Wink,et al.  Inhibition of cytochromes P450 by nitric oxide and a nitric oxide-releasing agent. , 1993, Archives of biochemistry and biophysics.

[37]  P. Needleman.  Organic nitrate metabolism. , 1976, Annual review of pharmacology and toxicology.