Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.
OBJECTIVE
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 micromol 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.


CONCLUSIONS
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.
Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Germany. schwedhelm@uke.uni-hamburg.de
Edzard
E
Schwedhelm
Renke
R
Maas
Ralf
R
Freese
Donald
D
Jung
Zoltan
Z
Lukacs
Alen
A
Jambrecina
William
W
Spickler
Friedrich
F
Schulze
Rainer H
RH
Böger
D000284:Administration, Oral; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D002956:Citrulline / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000187:drug effects*; D010919:Placebos; D014664:Vasodilation / Q000187:drug effects*
D010919:Placebos; D002956:Citrulline; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase