Cited by 494Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionAmino Acid Enzymes and Metabolism

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Pharmacokinetic and pharmacodynamic properties of oral L‐citrulline and L‐arginine: impact on nitric oxide metabolism

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Schwedhelm, Edzard, Maas, Renke, Freese, Ralf, Jung, Donald, Lukacs, Zoltan, Jambrecina, Alen, Spickler, William, Schulze, Friedrich, Böger, Rainer H.·2008·British Journal of Clinical Pharmacology

DOI 10.1111/j.1365-2125.2007.02990.xPMC PMC2291275

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Abstract

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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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
ORCID: Schwedhelm, Edzard
Maas, Renke
Jambrecina, Alen
Schulze, Friedrich
Böger, Rainer H.
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
DOI: 10.1111/j.1365-2125.2007.02990.x
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
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
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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Pharmacokinetic and pharmacodynamic properties of oral L‐citrulline and L‐arginine: impact on nitric oxide metabolism

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