Pharmacokinetics of Sodium Nitrite-Induced Methemoglobinemia in the Rat

Abstract

ABSTRACT:A biologically based mathematical model was created to characterize time and dose-dependent relationships between exposure to nitrite and induction of methemoglobinemia. The model includes mass action equations for processes known to occur: oral absorption of nitrite, elimination from the plasma, partitioning between plasma and erythrocytes, binding of nitrite to hemoglobin and methemoglobin, and the free radical chain reaction for hemoglobin oxidation. The model also includes Michaelis-Menten kinetics for methemoglobin reductase-catalyzed regeneration of hemoglobin. Body weight-scaled rate constants for absorption (k a ) and elimination (k e ), the effective erythrocyte/plasma partition coefficient (P), and the apparent K m for methemoglobin reductase were the only parameters estimated by formal optimization to reproduce the observed time course data. Time courses of plasma nitrite concentrations and blood levels of hemoglobin and methemoglobin in male and female rats that had received single intravenous or oral doses of sodium nitrite were measured. Peak plasma levels of nitrite were achieved in both sexes approximately 30 min after oral exposure, and peak methemoglobin levels were achieved after 100 min. The model predicts that 10% of the hemoglobin is oxidized to the ferric form after oral doses of 15.9 mg/kg in male rats and 11.0 mg/kg in female rats and after intravenous doses of 8.9 and 7.1 mg/kg in male and female rats, respectively. The t 1/2 for recovery from methemoglobinemia was 60 to 120 min depending on dose and route of administration. A sensitivity analysis of the model was performed to identify to which parameters the predictions of the model were most sensitive and guide attempts to simplify the model. Replacement of the V max of methemoglobin reductase with a value representative of humans predicted a 10% methemoglobinemia following an intravenous dose of 5.8 mg/kg, in close agreement with an observed value of 5.7 mg/kg for humans.

Nitrite confers protection against myocardial infarction: Role of xanthine oxidoreductase, NADPH oxidase and KATP channels

“…Previous pharmacokinetic studies of nitrite in the rat [24] predict a plasma concentration of 30 μM 15 minutes after intravenous administration at the optimal dose of 4 mg/kg. Thirty micromolar nitrite conferred cardioprotection in our in vitro studies.…”

The Reaction between Nitrite and Oxyhemoglobin

“…Titov and Petrenko (2) could not induce considerable hemoglobin oxidation in erythrocyte lysate by submillimolar levels of nitrite without addition of high levels of H 2 O 2 . On the other hand, as a consequence of poisoning, the nitrite level in plasma may reach 100 -400 M resulting in severe methemoglobinemia (1,34). The gastrointestinal absorption of nitrite is quick and complete, following by a rapid NO 2 decay accompanied with fast development of the maximal metHb level in plasma (35).…”

“…Elevated levels of nitrite in blood can trigger the oxidation of hemoglobin, leading to methemoglobinemia (1,2). The mechanism of nitrite-dependent oxidation of deoxyhemoglobin (deoxyHb) 2 under anaerobic conditions, and its physiological potential in hypoxic vasodilation has recently been established (3)(4)(5).…”

Secondary poisoning risk for encapsulated sodium nitrite, a new tool for possum control

“…Nitrites are seldom found at detectable levels in tissues and bodily fluids following consumption and are unlikely to accumulate in tissues; it is hypothesised that this is due to the rapid oxidation of nitrite to nitrate and the rapid and extensive excretion of nitrite (Walker 1996;European Food Safety Authority 2009). The scientific literature on the pharmacokinetics (depletion rates) demonstrates that NaNO 2 is rapidly excreted, with plasma elimination half-life values under 1 hour for numerous species of mammals (Schneider & Yeary 1975;Kohn et al 2002). This characteristic, coupled with NaNO 2 being less toxic than most other vertebrate pesticides, could be viewed as being indicative of a low risk of secondary poisoning (Boink & Speijers 2001).…”

“…However, there was no significant time × group interaction (F( 6,21 )=2.18, P = 0.153) and no significant difference between treatment groups (F( 2,7 )=1.78, P = 0.237). acute toxicity of NaNO 2 versus other vertebrate toxic agents and the rapid excretion of NaNO 2 (Kohn et al 2002;MRI 2004 . As well as no obvious signs of methaemoglobinaemia being observed in dogs, cats or chickens, the blood chemistry parameters analysed for dogs and cats indicated that after they consumed possum carcasses their liver and renal function remained normal and there was no damage to muscle tissue.…”