In vivo disposition of 3-nitro-L-tyrosine in rats: implications on tracking systemic peroxynitrite exposure.
In many pathological conditions such as inflammatory and neurodegenerative diseases, the in vivo toxicity of nitric oxide has been attributed to the toxic oxidant peroxynitrite. Interaction of peroxynitrite with biological molecules can modify tyrosine residues on the proteins at the ortho position resulting in the formation of the stable end-product, 3-nitro-L-tyrosine (3-NT). Recent investigations indicate that changes in the circulating concentrations of 3-NT in pathological conditions may reflect the extent of nitric oxide-dependent oxidative damage and peroxynitrite toxicity. In the present study, we examined the in vivo disposition characteristics of 3-NT in rats after either a single i.v. bolus dose (10 mg/kg) or a loading and maintenance infusion at 10 or 30 mg/kg. Plasma concentrations of 3-NT were analyzed by a reversed-phase HPLC method. After a single bolus dose of 3-NT at 10 mg/kg, the average half-life of the elimination phase for the drug was 68.5+/-18.4 min (n = 5). Infusions of 3-NT at two different doses (10 and 30 mg/kg) indicated that the pharmacokinetic properties of 3-NT below plasma concentrations of 100 microM were both linear and stationary. Urinary excretion of unchanged 3-NT was minimal, but two distinct metabolites of 3-NT were identified in the urine collected throughout the study. These findings may be useful in the interpretation of the plasma and urine 3-NT concentrations as possible indices of systemic peroxynitrite exposure.
Tabrizi-Fard
M A
MA
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260-1200, USA.
Maurer
T S
TS
Fung
H L
HL
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007262:Infusions, Intravenous; D008297:Male; D009566:Nitrates / Q000493:pharmacokinetics* / Q000633:toxicity*; D016877:Oxidants / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
D009566:Nitrates; D016877:Oxidants; C039642:peroxynitric acid; C002744:3-nitrotyrosine; D014443:Tyrosine