Single-Dose Pharmacokinetics of Different Oral Sodium Nitrite Formulations in Diabetes Patients

Background: Diabetic foot ulcers, although associated with macrovascular disease and neuropathy, have a microvascular disease causing ischemia not amenable to surgical intervention. Nitrite selectively releases nitric oxide in ischemic tissues, and diabetes subjects have low nitrite levels that do not increase with exercise. This study explores the safety and pharmacokinetics of a single dose of sodium nitrite in subjects with diabetic foot ulcers. Subjects and Methods: Using a blinded, randomized crossover study design, 12 subjects with diabetes mellitus and active or healed foot ulcers received a single dose of sodium nitrite on two occasions 7-28 days apart, once with an immediate release (IR) formulation and once with an enteric-coated (EC) formulation for delayed release. Serum nitrite, nitrate, methemoglobin, sulfhemoglobin, blood pressure, pulse rate, complete blood count, chemistry panel, electrocardiogram, and adverse events were followed for up to 6 h after each dose. The IR and EC nitrite levels were analyzed by one-way analysis of variance and by pharmacokinetic modeling. Results: The IR formulation elevated nitrite levels between 0.25 and 0.75 h (P < 0.05). The EC formulation did not elevate nitrite levels significantly, but both formulations gave plasma nitrite levels previously suggested to be therapeutic (approximately 2-5 mu M). The IR formulation gave an asymptomatic blood pressure drop of 10/6 mm Hg (P < 0.003), and two subjects experienced mild flushing. There was no elevation of methemoglobin or other safety concerns. Pharmacokinetic modeling of plama nitrite levels gave r(2) values of 0.81 and 0.97 for the fits for IR and EC formulations, respectively. Conclusions: Oral sodium nitrite administration is well tolerated in diabetes patients.