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

Abstract

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 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.

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.

Figures

Figure 1

Study design

Figure 2

Plasma concentrations of L-arginine at steady state (mean ± SEM, n = 17 for arginine immediate-release (IR) and n = 20 for all others). (A) Placebo (♦) curve. (B) After 1 week of 0.75 (▪), 1.5 (▴) and 3 g (•) twice-daily citrulline supplementation. (C) After 1 week of 1.0 g (▴) tid arginine IR and 1.6 g (•) bid arginine sustained-release supplementation

Figure 3

Change in pharmacodynamic parameters after 1 week of 1.6 g bid arginine sustained-release (SR) and 3 g bid citrulline in 20 healthy subjects. Change in (A) L-arginine/asymmetric dimethylarginine ratio, (B) urinary nitrate, (C) urinary cyclic guanosine monophosphate and (D) flow-mediated vasorelaxation (FMD). Individual changes and changes of the mean ± SEM are illustrated. Only statistically significant P-values are given

Figure 4

Cumulative data over all treatments. Mean change of flow-mediated vasorelaxation (FMD) is correlated with the mean change of L-arginine/asymmetric dimethylarginine ratio (Pearson's correlation, r = 0.92, P = 0.01, 95% confidence intervals indicated)