Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.
Level 2 - randomized trial
Individual randomized crossover trial
PubMed 17662090 · doi:10.1111/j.1365-2125.2007.02990.x
What was done
In a double-blind, randomized, placebo-controlled crossover trial, 20 healthy volunteers completed six different 1-week dosing regimens of placebo, L-citrulline, and L-arginine. Pharmacokinetic parameters (Cmax, Tmax, Cmin, AUC) of plasma L-arginine were evaluated. Measured pharmacodynamic endpoints included the plasma L-arginine to asymmetric dimethylarginine (ADMA) ratio, urinary nitrate and cyclic guanosine monophosphate (cGMP) excretion rates, and flow-mediated vasodilation (FMD).
What was found
Oral L-citrulline dose-dependently increased plasma L-arginine AUC and Cmax more effectively than oral L-arginine (P < 0.01). The highest dose of L-citrulline (3 g twice daily) increased plasma L-arginine Cmin, increased the L-arginine/ADMA ratio from 186 ± 8 to 278 ± 14 (P < 0.01, 95% CI 66, 121), increased urinary nitrate excretion from 92 ± 10 to 125 ± 15 µmol mmol(-1) creatinine (P = 0.01, 95% CI 8, 58), and increased urinary cGMP excretion from 38 ± 3.3 to 50 ± 6.7 nmol mmol(-1) creatinine (P = 0.04, 95% CI 0.4, 24). No treatment improved FMD over baseline, though pooled analysis showed a correlation between increased arginine/ADMA ratio and FMD improvement.
Why it matters
Oral L-citrulline increases systemic L-arginine concentrations and downstream nitric oxide signaling markers more effectively than direct oral L-arginine administration.
Limits
The trial included a small sample size of only 20 healthy participants with intact baseline endothelial function, limiting generalizability to clinical populations with endothelial dysfunction. Interventions were short (1 week per regimen), and no treatment improved flow-mediated vasodilation over baseline.
Cited by
- supports Supplemental oral arginine has poor bioavailability compared to citrulline for raising nitric oxide levels.