Document Type


Publication Date



70117487 (Orcid)


Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. L-arginine, an endogenous amino acid, was reported in clinical studies in adults to improve cardiovascular function in hypertension, pulmonary hypertension, pre-eclampsia, angina, and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. L-citrulline, a natural precursor of L-arginine, is more bioavailable than L-arginine because of hepatic first-pass metabolism avoidance and longer circulation time. Although not yet well studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases of children. However, optimal clinical development of arginine or citrulline in children is dependent on more information about pharmacokinetics and exposure-response relationships at appropriate ages and under relevant disease states. This article summarizes the pre-clinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as baseline variation of arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are not enough to inform the optimal design of clinical studies, especially those in children. Successful bench to bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic-pharmacodynamic studies, along with pharmacometric approaches.


The publisher's final edited version of this article is available at Paediatr Drugs.



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