Skip to main content
×
Home

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

  • C. Moinard (a1), I. Nicolis (a2), N. Neveux (a1) (a3), S. Darquy (a1), S. Bénazeth (a2) and L. Cynober (a1) (a3)...
Abstract

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) μmol/l (ARG) and 81 (sem 4) to 179 (sem 10) μmol/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.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study
      Available formats
      ×
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about sending content to Dropbox.

      Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study
      Available formats
      ×
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about sending content to Google Drive.

      Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study
      Available formats
      ×
Copyright
Corresponding author
*Corresponding author: Dr Christophe Moinard, fax +33 1 53 73 97 56, email christophe.moinard@univ-paris5.fr
References
Hide All
1 Curis E, Nicolis I, Moinard C, Osowska S, Zerrouk N, Benazeth S & Cynober L (2005) Almost all about citrulline in mammals. Amino Acids 29, 177205.
2 Rabier D & Kamoun P (1995) Metabolism of citrulline in man. Amino Acids 9, 299316.
3 Windmueller HG & Spaeth AE (1981) Source and fate of circulating citrulline. Am J Physiol 241, E473E480.
4 Castillo L, Sanchez M, Vogt J, Chapman TE, DeRojas-Walker TC, Tannenbaum SR, Ajami AM & Young VR (1995) Plasma arginine, citrulline, and ornithine kinetics in adults, with observations on nitric oxide synthesis. Am J Physiol 268, E360E367.
5 Castillo L, Chapman TE, Sanchez M, Yu YM, Burke JF, Ajami AM, Vogt J & Young VR (1993) Plasma arginine and citrulline kinetics in adults given adequate and arginine-free diets. Proc Natl Acad Sci USA 90, 77497753.
6 Cynober L, Le Boucher J & Vasson MP (1995) Arginine metabolism in mammals. J Nutr Biochem 6, 402413.
7 Drotman RB & Freedland RA (1972) Citrulline metabolism in the perfused rat liver. Am J Physiol 222, 973975.
8 Palmer RM, Ashton DS & Moncada S (1988) Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature 333, 664666.
9 Crenn P, Vahedi K, Lavergne-Slove A, Cynober L, Matuchansky C & Messing B (2003) Plasma citrulline: a marker of enterocyte mass in villous atrophy-associated small bowel disease. Gastroenterology 124, 12101219.
10 Crenn P, Coudray-Lucas C, Thuillier F, Cynober L & Messing B (2000) Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. Gastroenterology 119, 14961505.
11 Gondolesi G, Fishbein T, Chehade M, Tschernia A, Magid M, Kaufman S, Raymond K, Sansaricq C & LeLeiko N (2002) Serum citrulline is a potential marker for rejection of intestinal allografts. Transplant Proc 34, 918920.
12 Jianfeng G, Weiming Z, Ning L, Fangnan L, Li T, Nan L & Jieshou L (2005) Serum citrulline is a simple quantitative marker for small intestinal enterocytes mass and absorption function in short bowel patients. J Surg Res 127, 177182.
13 Lutgens LC, Deutz NE, Gueulette J, Cleutjens JP, Berger MP, Wouters BG, von Meyenfeldt MF & Lambin P (2003) Citrulline: a physiologic marker enabling quantitation and monitoring of epithelial radiation-induced small bowel damage. Int J Radiat Oncol Biol Phys 57, 10671074.
14 Wakabayashi Y (2004) The glutamate crossway. In Metabolic and Therapeutic Aspects of Amino Acids in Clinical Nutrition, pp. 135152 [Cynober L, editor]. Boca Raton, FL: CRC Press.
15 Wu G & Meininger CJ (2000) Arginine nutrition and cardiovascular function. J Nutr 130, 26262629.
16 Bansal V, Rodriguez P, Wu G, Eichler DC, Zabaleta J, Taheri F & Ochoa JB (2004) Citrulline can preserve proliferation and prevent the loss of CD3 zeta chain under conditions of low arginine. J Parenter Enteral Nutr 28, 423430.
17 Romero MJ, Platt DH, Caldwell RB & Caldwell RW (2006) Therapeutic use of citrulline in cardiovascular disease. Cardiovasc Drug Rev 24, 275290.
18 Waugh WH, Daeschner CW III, Files BA, McConnell ME & Strandjord SE (2001) Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. J Natl Med Assoc 93, 363371.
19 Akashi K, Miyake C & Yokota A (2001) Citrulline, a novel compatible solute in drought-tolerant wild watermelon leaves, is an efficient hydroxyl radical scavenger. FEBS Lett 508, 438442.
20 Osowska S, Moinard C, Neveux N, Loï C & Cynober L (2004) Citrulline increases arginine pools and restores nitrogen balance after massive intestinal resection. Gut 53, 17811786.
21 Farges MC, Vasson MP & Cynober L (1997) Aging of the small bowel: relationship between morphological and functional changes and protein metabolism. J Nutr Health Aging 1, 1722.
22 Osowska S, Duchemann T, Walrand S, Paillard A, Boirie Y, Cynober L & Moinard C (2006) Citrulline modulates muscle protein metabolism in old malnourished rats. Am J Physiol Endocrinol Metab 291, E582E586.
23 Rajantie J, Simell O & Perheentupa J (1983) Oral administration of urea cycle intermediates in lysinuric protein intolerance: effect on plasma and urinary arginine and ornithine. Metabolism 32, 4951.
24 Collins JK, Wu G, Perkins-Veazie P, Spears K, Claypool PL, Baker RA & Clevidence BA (2007) Watermelon consumption increases plasma arginine concentrations in adults. Nutrition 23, 261266.
25 Cynober L (2007) Pharmacokinetics of arginine and related amino acids. J Nutr 137, Suppl. 2, 1646S1649S.
26 Mandel H, Levy N, Izkovitch S & Korman SH (2005) Elevated plasma citrulline and arginine due to consumption of Citrullus vulgaris (watermelon). J Inherit Metab Dis 28, 467472.
27 Rimando AM & Perkins-Veazie PM (2005) Determination of citrulline in watermelon rind. J Chromatogr A 1078, 196200.
28 Wu G, Knabe DA & Kim SW (2004) Arginine nutrition in neonatal pigs. J Nutr 134, Suppl. 10, 2783S2790S.
29 Urschel KL, Shoveller AK, Uwiera RR, Pencharz PB & Ball RO (2006) Citrulline is an effective arginine precursor in enterally fed neonatal piglets. J Nutr 136, 18061813.
30 Smith HA, Canter JA, Christian KG, Drinkwater DC, Scholl FG, Christman BW, Rice GD, Barr FE & Summar ML (2006) Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline. J Thorac Cardiovasc Surg 132, 5865.
31 Vagdagama JV & Evered DF (1992) Characteristics of l-citrulline transport across rat small intestine in vitro. Pediatr Res 32, 472478.
32 Grimble GK (2007) Adverse GI effects of arginine and related amino acids. J Nutr 137, 1693S1701S.
33 Collier SR, Casey DP & Kanaley JA (2005) Growth hormone responses to varying doses of oral arginine. Growth Horm IGF Res 15, 136139.
34 Cynober L, Vaubourdolle M, Dore A & Giboudeau J (1984) Kinetics and metabolic effects of orally administered ornithine α-ketoglutarate in healthy subjects fed with a standardized regimen. Am J Clin Nutr 39, 514519.
35 Cynober L, Coudray-Lucas C, De Bandt JP, Guéchot J, Aussel C, Salvucci M & Giboudeau J (1990) Action of ornithine α-ketoglutarate, ornithine hydrochloride, and calcium α-ketoglutarate on plasma amino acid and hormonal patterns in healthy subjects. J Am Coll Nutr 9, 212.
36 Tangphao O, Grossmann M, Chalon S, Hoffman BB & Blaschke TF (1999) Pharmacokinetics of intravenous and oral l-arginine in normal volunteers. Br J Clin Pharmacol 47, 261266.
37 Daly JM, Reynolds J, Thom A, Kinsley L, Dietrick-Gallager M, Shou J & Ruggieri B (1988) Immune and metabolic effects of arginine in the surgical patient. Ann Surg 208, 512523.
38 Vaubourdolle M, Cynober L, Lioret N, Coudray-Lucas C, Aussel C, Saizy R & Giboudeau J (1987) Influence of enterally administered ornithine α-ketoglutarate on hormonal patterns in burn patients. Burns 13, 349356.
39 Barbul A (1995) The use of arginine in clinical practice. In Amino Acid Metabolism and Therapy in Health and Nutritional Disease, pp. 361375 [Cynober L, editor]. Boca Raton, FL: CRC Press.
40 Neveux N, David P & Cynober L (2004) Measurement of amino acid concentration in biological fluids and tissues using ion-exchange chromatography. In Metabolic and Therapeutic Aspects of Amino Acids in Clinical Nutrition, pp. 1728 [Cynober L, editor]. Boca Raton, FL: CRC Press.
41 Grimble G (1991) Measurement of elemental nitrogen by chemiluminescence (letter; comment). J Parenter Enteral Nutr 15, 696.
42 Blanc MC, Neveux N, Laromiguiere M, Berard MP & Cynober L (2000) Evaluation of a newly available biochemical analyzer: the Olympus AU 600. Clin Chem Lab Med 38, 465475.
43 R Development Core Team (2005) A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing.
44 Sakamoto Y, Ishiguro M & Kitagawa G (1986) Akaike Information Criterion Statistics. Dordrecht, The Netherlands: D. Reidel Publishing Company.
45 Curis E, Crenn P & Cynober L (2007) Citrulline and the gut. Curr Opin Clin Nutr Metab Care 10, 620626.
46 Levillain O, Parvy P & Hassler C (1997) Amino acid handling in uremic rats: citrulline, a reliable marker of renal insufficiency and proximal tubular dysfunction. Metabolism 46, 611618.
47 Moinard C & Cynober L (2007) Citrulline: a new player in the control of nitrogen homeostasis. J Nutr 137, Suppl. 2, 1621S1625S.
48 Wu G & Meininger CJ (1993) Regulation of l-arginine synthesis from l-citrulline by l-glutamine in endothelial cells. Am J Physiol 265, H1965H1971.
49 Wu G & Brosnan JT (1992) Macrophages can convert citrulline into arginine. Biochem J 281, 4548.
50 Bahri S, Zerrouk N, Curis E, et al. (2005) Characterization of l-citrulline transport in human intestinal caco-2 cells. Clin Nutr 24, 630.
51 Bengoa JM, Sitrin MD, Wood RJ & Rosenberg IH (1983) Amino acid-induced hypercalciuria in patients on total parenteral nutrition. Am J Clin Nutr 38, 264269.
52 Wu G (1998) Intestinal mucosal amino acid catabolism. J Nutr 128, 12491252.
53 Vaubourdolle M, Jardel A, Coudray-Lucas C, Ekindjian OG, Agneray J & Cynober L (1988) Metabolism and kinetics of parenterally administered ornithine and α-ketoglutarate in healthy and burned animals. Clin Nutr 7, 105111.
54 Vaubourdolle M, Jardel A, Coudray-Lucas C, Ekindjian OG, Agneray J & Cynober L (1989) Fate of enterally administered ornithine in healthy animals: interactions with α-ketoglutarate. Nutrition 5, 183187.
55 De Bandt JP, Cynober L, Lim SK, Coudray-Lucas C, Poupon R & Giboudeau J (1995) Metabolism of ornithine, α-ketoglutarate and arginine in isolated perfused rat liver. Br J Nutr 73, 227239.
56 Morris SM Jr (2006) Arginine: beyond protein. Am J Clin Nutr 83, 508S512S.
57 Dhanakoti SN, Brosnan JT, Herzberg GR & Brosnan ME (1990) Renal arginine synthesis: studies in vitro and in vivo. Am J Physiol 259, E437E442.
58 Nakata M & Yada T (2003) Nitric oxide-mediated insulin secretion in response to citrulline in islet β-cells. Pancreas 27, 209213.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords:

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 23
Total number of PDF views: 146 *
Loading metrics...

Abstract views

Total abstract views: 705 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 24th November 2017. This data will be updated every 24 hours.