Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.
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Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. / Schwedhelm, Edzard; Maas, Renke; Freese, Ralf; Jung, Donald; Lukacs, Zoltan; Jambrecina, Alen; Spickler, William; Schulze, Friedrich; Böger, Rainer.
in: BRIT J CLIN PHARMACO, Jahrgang 65, Nr. 1, 1, 2008, S. 51-59.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.
AU - Schwedhelm, Edzard
AU - Maas, Renke
AU - Freese, Ralf
AU - Jung, Donald
AU - Lukacs, Zoltan
AU - Jambrecina, Alen
AU - Spickler, William
AU - Schulze, Friedrich
AU - Böger, Rainer
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 65
SP - 51
EP - 59
JO - BRIT J CLIN PHARMACO
JF - BRIT J CLIN PHARMACO
SN - 0306-5251
IS - 1
M1 - 1
ER -