Characterization of erythrocytic uptake and release and disposition pathways of nitrite, nitrate, methemoglobin, and iron-nitrosyl hemoglobin in the human circulation.

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Yuen Yi HonMark T Gladwin

Abstract

Nitrite-hemoglobin reactions have been studied extensively in vitro, but there is a lack of information on the kinetics of nitrite and its metabolites in humans. In this study, we developed a nine-compartment physiological pharmacokinetic model to describe the in vivo erythrocytic uptake and release and disposition pathways of nitrite, nitrate, methemoglobin, and iron-nitrosyl hemoglobin in the human circulation. Our model revealed that nitrite entered erythrocytes rapidly with a rate constant of 0.256 min(-1) (i.e., half-life = 2.71 min). The formation of iron-nitrosyl hemoglobin from nitrite, which involves the reduction of nitrite by deoxyhemoglobin to generate nitric oxide (NO) and reaction of NO with deoxyhemoglobin to form iron-nitrosyl hemoglobin, occurred rapidly as well (k = 2.02 min(-1); half-life = 0.343 min = 21 s). The disposition kinetics of methemoglobin was complex. Nitrate formation occurred primarily in erythrocytes through the nitrite-oxyhemoglobin reaction and was higher when nitrite was administered intra-arterially than intravenously. Nitrate reduction was an insignificant metabolic pathway. This study is the first to comprehensively evaluate the kinetics of nitrite and its metabolites in humans and provid...Continue Reading

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Citations

Aug 25, 2012·Free Radical Biology & Medicine·Andrey A SamalRakesh P Patel
Nov 28, 2017·The Tohoku Journal of Experimental Medicine·Hyunyoung LimGaabsoo Kim
Mar 20, 2014·Circulation Research·Tienush RassafMalte Kelm
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Jun 16, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jan ScicinskiWilliam L Fitch
Jan 11, 2014·Journal of Applied Physiology·Amy L SindlerDouglas R Seals
May 19, 2020·Journal of Cardiovascular Pharmacology·Yusuke Miyazaki, Fumito Ichinose
Nov 4, 2017·Scientific Reports·Kathleen CantowErdmann Seeliger
Jun 14, 2019·Dose-response : a Publication of International Hormesis Society·Hoon JungDong Gun Lim

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