Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study

Br J Nutr. 2008 Apr;99(4):855-62. doi: 10.1017/S0007114507841110. Epub 2007 Oct 22.


Previous experimental studies have highlighted that citrulline (CIT) could be a promising pharmaconutrient. However, its pharmacokinetic characteristics and tolerance to loading have not been studied to date. The objective was to characterise the plasma kinetics of CIT in a multiple-dosing study design and to assess the effect of CIT intake on the concentrations of other plasma amino acids (AA). The effects of CIT loading on anabolic hormones were also determined. Eight fasting healthy males underwent four separate oral loading tests (2, 5, 10 or 15 g CIT) in random order. Blood was drawn ten times over an 8 h period for measurement of plasma AA, insulin and growth hormone (Gh). Urine samples were collected before CIT administration and over the next 24 h. None of the subjects experienced side effects whatever the CIT dose. Concerning AA, only CIT, ornithine (ORN) and arginine (ARG) plasma concentrations were affected (maximum concentration 146 (sem 8) to 303 (sem 11) micromol/l (ARG) and 81 (sem 4) to 179 (sem 10) micromol/l (ORN); time to reach maximum concentration 1.17 (sem 0.26) to 2.29 (sem 0.20) h (ARG) and 1.38 (sem 0.25) to 1.79 (sem 0.11) h (ORN) according to CIT dose). Even at high doses, urinary excretion of CIT remained low ( < 5 %). Plasma insulin and Gh were not affected by CIT administration. Short-term CIT administration is safe and well-tolerated. CIT is a potent precursor of ARG. However, at the highest doses, CIT accumulated in plasma while plasma ARG levels increased less than expected. This may be due to saturation of the renal conversion of CIT into ARG.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acids / blood*
  • Amino Acids / urine
  • Analysis of Variance
  • Area Under Curve
  • Arginine / blood
  • Blood Glucose / analysis
  • Calcium / blood
  • Citrulline / administration & dosage
  • Citrulline / pharmacokinetics*
  • Creatinine / blood
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Tolerance
  • Growth Hormone / blood*
  • Humans
  • Insulin / blood*
  • Kidney / metabolism*
  • Male
  • Metabolic Clearance Rate
  • Nitrogen / urine
  • Ornithine / blood


  • Amino Acids
  • Blood Glucose
  • Insulin
  • Citrulline
  • Growth Hormone
  • Arginine
  • Creatinine
  • Ornithine
  • Nitrogen
  • Calcium