Department of Pharmaceutical Sciences, College of Pharmacy, the University of Oklahoma Health Sciences Center, Oklahoma, USA.
CPT Pharmacometrics Syst Pharmacol. 2013 Jul 31;2(7):e60. doi: 10.1038/psp.2013.35.
A long-term sodium nitrite infusion is intended for the treatment of vascular disorders. Phase I data demonstrated a significant nonlinear dose-exposure-toxicity relationship within the therapeutic dosage range. This study aims to develop a quantitative systems pharmacology model characterizing nitric oxide (NO) metabolome and methemoglobin after sodium nitrite infusion. Nitrite, nitrate, and methemoglobin concentration-time profiles in plasma and RBC were used for model development. Following intravenous sodium nitrite administration, nitrite undergoes conversion in RBC and tissue. Nitrite sequestered by RBC interacts more extensively with deoxyhemoglobin, which contributes greatly to methemoglobin formation. Methemoglobin is formed less-than-proportionally at higher nitrite doses as characterized with facilitated methemoglobin removal. Nitrate-to-nitrite reduction occurs in tissue and via entero-salivary recirculation. The less-than-proportional increase in nitrite and nitrate exposure at higher nitrite doses is modeled with a dose-dependent increase in clearance. The model provides direct insight into NO metabolome disposition and is valuable for nitrite dosing selection in clinical trials.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e60; doi:10.1038/psp.2013.35; published online 31 July 2013.
长期亚硝酸钠输注旨在治疗血管疾病。I 期数据表明，在治疗剂量范围内，存在显著的非线性剂量-暴露-毒性关系。本研究旨在建立一种定量系统药理学模型，以描述亚硝酸钠输注后一氧化氮（NO）代谢组和高铁血红蛋白的变化。模型开发使用了血浆和 RBC 中硝酸盐、亚硝酸盐和高铁血红蛋白的浓度-时间曲线。静脉注射亚硝酸钠后，亚硝酸盐在 RBC 和组织中转化。与脱氧血红蛋白相互作用的 RBC 中亚硝酸盐更多，这对高铁血红蛋白的形成有很大贡献。高铁血红蛋白的形成不成比例地增加，这与高铁血红蛋白的清除增加有关。硝酸盐在组织中和通过肠-唾液再循环转化为亚硝酸盐。随着亚硝酸盐剂量的增加，亚硝酸盐和硝酸盐的暴露呈不成比例的增加，这是通过清除率的剂量依赖性增加来模拟的。该模型提供了对 NO 代谢组处置的直接了解，对于临床试验中的亚硝酸钠剂量选择很有价值。CPT：药效学和系统药理学（2013 年）2，e60；doi：10.1038/psp.2013.35；在线发表 2013 年 7 月 31 日。
