Simultaneous Pharmacokinetic Analysis of Nitrate and its Reduced Metabolite, Nitrite, Following Ingestion of Inorganic Nitrate in a Mixed Patient Population

Andrew R. Coggan, Susan B. Racette, Dakkota Thies, Linda R. Peterson, Robert E. Stratford

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Purpose: The pharmacokinetic properties of plasma NO3 and its reduced metabolite, NO2, have been separately described, but there has been no reported attempt to simultaneously model their pharmacokinetics following NO3 ingestion. This report describes development of such a model from retrospective analyses of concentrations largely obtained from primary endpoint efficacy trials. Methods: Linear and non-linear mixed effects analyses were used to statistically define concentration dependency on time, dose, as well as patient and study variables, and to integrate NO3 and NO2 concentrations from studies conducted at different times, locations, patient groups, and several studies in which sample range was limited to a few hours. Published pharmacokinetic studies for both substances were used to supplement model development. Results: A population pharmacokinetic model relating NO3 and NO2 concentrations was developed. The model incorporated endogenous levels of the two entities, and determined these were not influenced by exogenous NO3 delivery. Covariate analysis revealed intersubject variability in NO3 exposure was partially described by body weight differences influencing volume of distribution. The model was applied to visualize exposure versus response (muscle contraction performance) in individual patients. Conclusions: Extension of the present first-generation model, to ultimately optimize NO3 dose versus pharmacological effects, is warranted.

Original languageEnglish
Article number235
JournalPharmaceutical Research
Volume37
Issue number12
DOIs
StatePublished - Dec 1 2020

Keywords

  • Nitric oxide
  • isokinetic dynamometry
  • nitrate
  • nitrite
  • pharmacokinetics

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