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Pharmacokinetic and pharmacodynamic properties of oral L‐citrulline and L‐arginine: impact on nitric oxide metabolism
Author(s) -
Schwedhelm Edzard,
Maas Renke,
Freese Ralf,
Jung Donald,
Lukacs Zoltan,
Jambrecina Alen,
Spickler William,
Schulze Friedrich,
Böger Rainer H.
Publication year - 2008
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2007.02990.x
Subject(s) - asymmetric dimethylarginine , arginine , citrulline , pharmacokinetics , pharmacodynamics , nitric oxide , medicine , pharmacology , endocrinology , vasodilation , arginase , chemistry , biochemistry , amino acid
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.