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Pharmacokinetic and pharmacodynamic properties of oral L‐citrulline and L‐arginine: impact on nitric oxide metabolism
Open accessAbstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • L‐Arginine is a semiessential amino acid that is converted to nitric oxide (NO) by NO synthase (NOS). • NO improves endothelial function by elevating cyclic guanosine monophosphate. • However, oral L‐arginine treatment in humans is hampered by extensive metabolism. WHAT THIS STUDY ADDS • Oral L‐citrulline supplementation raises plasma L‐arginine concentration and augments NO‐dependent signalling in a dose‐dependent manner. • L‐Citrulline may thus be an alternative to L‐arginine in patients with impaired NOS activity. AIMS: Oral L‐arginine supplementation has been used in several studies to improve endothelium‐dependent, nitric oxide (NO)‐mediated vasodilation. L‐Arginine treatment is hampered by extensive presystemic elimination due to intestinal arginase activity. In contrast, L‐citrulline is readily absorbed and at least in part converted to L‐arginine. The aim of our study was to assess this metabolic conversion and its subsequent pharmacodynamic effects. METHODS: In a double‐blind, randomized, placebo‐controlled cross‐over study, 20 healthy volunteers received six different dosing regimes of placebo, citrulline, and arginine. Pharmacokinetic parameters ( C max , T max , C min , AUC) were calculated after 1 week of oral supplementation. The ratio of plasma L‐arginine over asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase (arginine/ADMA ratio), urinary cyclic guanosine monophosphate (cGMP) and nitrate excretion rates, and flow‐mediated vasodilation (FMD) was measured to assess pharmacodynamic effects. RESULTS: L‐Citrulline dose‐dependently increased AUC and C max of plasma L‐arginine concentration more effectively than L‐arginine ( P < 0.01). The highest dose of citrulline (3 g bid) increased the C min of plasma L‐arginine and improved the L‐arginine/ADMA ratio from 186 ± 8 (baseline) to 278 ± 14 [ P < 0.01, 95% confidence interval (CI) 66, 121]. Moreover, urinary nitrate and cGMP were increased from 92 ± 10 to 125 ± 15 µmol mmol −1 creatinine ( P = 0.01, 95% CI 8, 58) and from 38 ± 3.3 to 50 ± 6.7 nmol mmol −1 creatinine ( P = 0.04, 95% CI 0.4, 24), respectively. No treatment improved FMD over baseline. However, pooled analysis of all FMD data revealed a correlation between the increase of arginine/ADMA ratio and improvement of FMD. CONCLUSION: Our data show for the first time that oral L‐citrulline supplementation raises plasma L‐arginine concentration and augments NO‐dependent signalling in a dose‐dependent manner.
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“Due to this and its non-competitive uptake for cell transport [542], oral citrulline supplementation has been shown to be more effective in increasing arginine [543, 544] and activation of nitric oxide synthase (NOS) [544] as well as various biomarkers of nitric oxide [545].”
From ISSN exercise & sports nutrition review update: research & recommendations (2018) · cites this paper as [543]
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“Citrulline, the end product of arginine-mediated nitric oxide production, has shown the potential to increase plasma nitrate and NO availability (Schwedhelm et al. 2007; Morita et al. 2014).”
From Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure (2016) · cites this paper as Schwedhelm et al. 2007
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“supplementation of older adults with citrulline elevated plasma arginine concentrations for up to 6 h (Moinard et al. 2015; Schwedhelm et al. 2007)”
From Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure (2016) · cites this paper as Schwedhelm et al. 2007
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“and increased nitric oxide production in vivo (Churchward-Venne et al. 2014; Schwedhelm et al. 2007).”
From Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure (2016) · cites this paper as Schwedhelm et al. 2007
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“increases both plasma arginine and cGMP (Schwedhelm et al. 2007) and is free of side effects.”
From Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure (2016) · cites this paper as Schwedhelm et al. 2007
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Use of Tandem Mass Spectrometry for Multianalyte Screening of Dried Blood Specimens from Newborns
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Almost all about citrulline in mammals
Curis, E., Nicolis, I., Moinard, C., Osowska, S., Zerrouk, N., Bénazeth, S., & Cynober, L. (2005) · Amino Acids · doi:10.1007/s00726-005-0235-4 · Cited by 571
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Asymmetrical Dimethylarginine: The Über Marker?
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Morris, S. M. (2004) · Journal of Nutrition · doi:10.1093/jn/134.10.2743s · Cited by 361
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ISSN exercise & sports nutrition review update: research & recommendations
Kerksick, C. M., Wilborn, C. D., Roberts, M. D., Smith-Ryan, A., Kleiner, S. M., Jäger, R., Collins, R., Cooke, M., Davis, J. N., Galvan, E., et al. (2018) · Journal of the International Society of Sports Nutrition · doi:10.1186/s12970-018-0242-y · Cited by 945
Arginase: an emerging key player in the mammalian immune system
Munder, M. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00291.x · Cited by 725
Strategies to increase nitric oxide signalling in cardiovascular disease
Lundberg, J. O., Gladwin, M. T., & Weitzberg, E. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4623 · Cited by 576
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
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Role of L-Arginine in Nitric Oxide Synthesis and Health in Humans
Wu, G., Meininger, C. J., McNeal, C. J., Bazer, F. W., & Rhoads, J. M. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-74180-8_10 · Cited by 344
Metadata
- Authors
- Schwedhelm, E., Maas, R., Freese, R., Jung, D., Lukacs, Z., Jambrecina, A., Spickler, W., Schulze, F., & Böger, R. H.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- Corresponding author
- Schwedhelm, Edzard
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2007-10-22
- Volume
- 65
- Issue
- 1
- Pages
- 51-59
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC2291275
- OpenAlex
- W2162463567
- Cited by
- 494
- References
- 43
- Citations by year
- 2026: 19 · 2025: 31 · 2024: 22 · 2023: 47 · 2022: 42 · 2021: 48 · 2020: 42 · 2019: 30 · 2018: 27 · 2017: 24 · 2016: 32 · 2015: 33 · 2014: 27 · 2013: 16 · 2012: 16
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Clinical Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- citrulline, L-arginine, nitric oxide, nitric oxide synthase, asymmetric dimethylarginine, flow-mediated dilation, endothelial function, cyclic GMP, urinary nitrate, arginase, oral supplementation, pharmacokinetics, pharmacodynamics, dose-response relationship, nitric oxide metabolism, endothelium-dependent vasodilation
- MeSH terms
- Administration, Oral, Arginine, Citrulline, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Nitric Oxide, Placebos, Vasodilation, Cross-Over Studies, Nitric Oxide Synthase
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