Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review

Paediatr Drugs. 2020 Jun;22(3):279-293. doi: 10.1007/s40272-020-00384-5.

Abstract

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

Publication types

  • Review

MeSH terms

  • Adolescent
  • Adult
  • Arginine / pharmacology
  • Arginine / therapeutic use*
  • Child
  • Citrulline / pharmacology
  • Citrulline / therapeutic use*
  • Female
  • Humans
  • Male
  • Pharmacology, Clinical / methods*
  • Young Adult

Substances

  • Citrulline
  • Arginine