This report describes the results of a volunteer study on the oral bioavailability of sodium nitrite conducted by the National Poisons Information Center in the Netherlands.
Oral bioavailability refers to the proportion of an orally administered substance, such as a drug or compound, that enters the bloodstream in an active form. It is a measure of how effectively a substance can be absorbed and utilized when taken by mouth. Factors such as the substance's chemical properties, its interaction with the gastrointestinal tract, and potential metabolism in the liver can affect its oral bioavailability. A higher oral bioavailability indicates that a larger percentage of the substance reaches the systemic circulation, making it more effective when taken orally.
Seven female and two male volunteers participated in and completed the study.
All doses of sodium nitrite were administered after an overnight fast. Adverse effects, blood pressure, heart rate, hemoglobin concentration, the percentage of metHb in the blood, and plasma nitrite and nitrate concentrations were recorded after each administration of sodium nitrite. Headache was the most common complaint during each treatment session. After each treatment, a decrease in blood pressure was accompanied by an increase in heart rate.
The gastrointestinal absorption of sodium nitrite was very rapid. The peak plasma nitrite concentrations were observed between 15 and 30 minutes after the dose. Nitrite rapidly disappeared from the plasma. The average elimination half-life was approximately 30 minutes.
It can be concluded that, under fasting conditions, 90 to 95% of oral administered sodium nitrite is absorbed into the blood.
Download oral bioavailability of sodium nitrite:
https://www.rivm.nl/bibliotheek/rapporten/235802007.pdf
Pre-study
In blood nitrite is rapidly oxidized by hemoglobin to yield methemoglobin and nitrate. Calculating the oral bioavailability of nitrite from the plasma nitrite concentration is hampered and requires a substantial nitrite dose to be administered to healthy volunteers. Because of the vasodilating and methemoglobin inducing potential of nitrite there are limitations to the nitrite dose which can safely be administered to volunteers in a bioavailability study. The bioavailability study was preceded by a single , intravenous, ascending dose study to investigate the maximum nitrite dose which can safely be administered in vivo; i.e. inducing approximately 10 to 15% metHb. This study demonstrates that a sodium nitrite dose of 0.12 mmol NaNO2 per mmol Hb (between 290 and 370 mg) and inducing approximately 10.8% methemoglobin in the blood, is the maximum tolerated dose for adult volunteers.
Download (pre-study) Intravenous administration of sodium nitrite
https://www.rivm.nl/bibliotheek/rapporten/235802011.pdf
Adverse experiences
Throughout the study, volunteers were frequently asked about negative experiences in general terms. Participants were instructed to report all side effects, whether or not they were related to sodium nitrite.
During none of the treatment sessions were severe side effects observed. Most of the side effects were of mild intensity, except for one moderate-intensity headache and two cases of moderate nausea/vomiting. Of all the reported side effects, they were known to be associated with sodium nitrite. Headache was the most common complaint during each of the treatments.
Depending on the number of side effects, intravenous administration of sodium nitrite was the least well-tolerated (7 volunteers reported 12 side effects), followed by the high-dose oral administration of sodium nitrite (6 volunteers reported 9 side effects), and low-dose oral administration of sodium nitrite (4 volunteers reported 6 side effects).
Volunteers 7 and 9 were the only volunteers who reported no side effects related to sodium nitrite during any of the treatment sessions.
Volunteer 6 experienced nausea after both intravenous administration of sodium nitrite and high-dose oral administration of sodium nitrite. Since the nausea occurred after both intravenous and oral administration of sodium nitrite, it is likely that the nausea is a systemic effect of sodium nitrite rather than a localized stomach effect.
Peak plasma nitrite concentration
In five of the nine volunteers, the peak plasma nitrite concentration was observed 15 minutes after the dose for both oral treatments. In the other volunteers, the peak concentration was observed 30 or 45 minutes after the dose.
The term "peak plasma nitrite concentration" refers to the highest level of nitrite in the blood plasma after the administration of sodium nitrite.
This peak concentration is significant because it indicates when nitrite in the blood reaches its maximum level after ingestion.
Intragastric stability of nitrite
The intragastric stability of nitrite depends not only on the stomach's pH but also on the presence of specific compounds (food components) that react with nitrite.
Nitrite can be unstable in an acidic stomach environment. However, the doses administered in this study, dissolved in an aqueous solution after an overnight fast, seemed to pass through the stomach rapidly without significant degradation.
Formation of methemoglobin
In the study, methemoglobin concentration was measured as an alternative variable to calculate the oral biological availability of sodium nitrite based on (F=Dose nitrite iv/AUC metHb iv * AUC metHb po/ Dose nitrite po). For the oral dose of sodium nitrite equal to the intravenous dose, the biologic availability of nitrite calculated in this way ranged from 71 to 99%. This thus supports the observed high biological availability of nitrite, calculated based on plasma nitrite data. It also indicates that the route of exposure to nitrite, intravenous versus oral, does not influence the induced percentage of metHb.
When the dose of sodium nitrite was doubled, it resulted in a twofold increase in AUCnitrite. However, notably, the AUCmeth (methemoglobin) increased more than twofold after the same doubling of the sodium nitrite dose. This finding suggests that the relationship between dose and response may not be linear, which is crucial for understanding the impact of dose variations on methemoglobin formation in response to sodium nitrite.
Oral bioavailability refers to the proportion of an orally administered substance, such as a drug or compound, that enters the bloodstream in an active form. It is a measure of how effectively a substance can be absorbed and utilized when taken by mouth. Factors such as the substance's chemical properties, its interaction with the gastrointestinal tract, and potential metabolism in the liver can affect its oral bioavailability. A higher oral bioavailability indicates that a larger percentage of the substance reaches the systemic circulation, making it more effective when taken orally.
Seven female and two male volunteers participated in and completed the study.
All doses of sodium nitrite were administered after an overnight fast. Adverse effects, blood pressure, heart rate, hemoglobin concentration, the percentage of metHb in the blood, and plasma nitrite and nitrate concentrations were recorded after each administration of sodium nitrite. Headache was the most common complaint during each treatment session. After each treatment, a decrease in blood pressure was accompanied by an increase in heart rate.
The gastrointestinal absorption of sodium nitrite was very rapid. The peak plasma nitrite concentrations were observed between 15 and 30 minutes after the dose. Nitrite rapidly disappeared from the plasma. The average elimination half-life was approximately 30 minutes.
It can be concluded that, under fasting conditions, 90 to 95% of oral administered sodium nitrite is absorbed into the blood.
Download oral bioavailability of sodium nitrite:
https://www.rivm.nl/bibliotheek/rapporten/235802007.pdf
Pre-study
In blood nitrite is rapidly oxidized by hemoglobin to yield methemoglobin and nitrate. Calculating the oral bioavailability of nitrite from the plasma nitrite concentration is hampered and requires a substantial nitrite dose to be administered to healthy volunteers. Because of the vasodilating and methemoglobin inducing potential of nitrite there are limitations to the nitrite dose which can safely be administered to volunteers in a bioavailability study. The bioavailability study was preceded by a single , intravenous, ascending dose study to investigate the maximum nitrite dose which can safely be administered in vivo; i.e. inducing approximately 10 to 15% metHb. This study demonstrates that a sodium nitrite dose of 0.12 mmol NaNO2 per mmol Hb (between 290 and 370 mg) and inducing approximately 10.8% methemoglobin in the blood, is the maximum tolerated dose for adult volunteers.
Download (pre-study) Intravenous administration of sodium nitrite
https://www.rivm.nl/bibliotheek/rapporten/235802011.pdf
Adverse experiences
Throughout the study, volunteers were frequently asked about negative experiences in general terms. Participants were instructed to report all side effects, whether or not they were related to sodium nitrite.
During none of the treatment sessions were severe side effects observed. Most of the side effects were of mild intensity, except for one moderate-intensity headache and two cases of moderate nausea/vomiting. Of all the reported side effects, they were known to be associated with sodium nitrite. Headache was the most common complaint during each of the treatments.
Depending on the number of side effects, intravenous administration of sodium nitrite was the least well-tolerated (7 volunteers reported 12 side effects), followed by the high-dose oral administration of sodium nitrite (6 volunteers reported 9 side effects), and low-dose oral administration of sodium nitrite (4 volunteers reported 6 side effects).
Volunteers 7 and 9 were the only volunteers who reported no side effects related to sodium nitrite during any of the treatment sessions.
Volunteer 6 experienced nausea after both intravenous administration of sodium nitrite and high-dose oral administration of sodium nitrite. Since the nausea occurred after both intravenous and oral administration of sodium nitrite, it is likely that the nausea is a systemic effect of sodium nitrite rather than a localized stomach effect.
Peak plasma nitrite concentration
In five of the nine volunteers, the peak plasma nitrite concentration was observed 15 minutes after the dose for both oral treatments. In the other volunteers, the peak concentration was observed 30 or 45 minutes after the dose.
The term "peak plasma nitrite concentration" refers to the highest level of nitrite in the blood plasma after the administration of sodium nitrite.
This peak concentration is significant because it indicates when nitrite in the blood reaches its maximum level after ingestion.
Intragastric stability of nitrite
The intragastric stability of nitrite depends not only on the stomach's pH but also on the presence of specific compounds (food components) that react with nitrite.
Nitrite can be unstable in an acidic stomach environment. However, the doses administered in this study, dissolved in an aqueous solution after an overnight fast, seemed to pass through the stomach rapidly without significant degradation.
Formation of methemoglobin
In the study, methemoglobin concentration was measured as an alternative variable to calculate the oral biological availability of sodium nitrite based on (F=Dose nitrite iv/AUC metHb iv * AUC metHb po/ Dose nitrite po). For the oral dose of sodium nitrite equal to the intravenous dose, the biologic availability of nitrite calculated in this way ranged from 71 to 99%. This thus supports the observed high biological availability of nitrite, calculated based on plasma nitrite data. It also indicates that the route of exposure to nitrite, intravenous versus oral, does not influence the induced percentage of metHb.
When the dose of sodium nitrite was doubled, it resulted in a twofold increase in AUCnitrite. However, notably, the AUCmeth (methemoglobin) increased more than twofold after the same doubling of the sodium nitrite dose. This finding suggests that the relationship between dose and response may not be linear, which is crucial for understanding the impact of dose variations on methemoglobin formation in response to sodium nitrite.
