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L‐arginine‐induced vasodilation in healthy humans:pharmacokinetic–pharmacodynamic relationship
Author(s) -
BodeBöger Stefanie M.,
Böger Rainer H.,
Galland Andrea,
Tsikas Dimitrios,
Frölich Jürgen C.
Publication year - 1998
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 - 10.1046/j.1365-2125.1998.00803.x
Subject(s) - pharmacokinetics , bioavailability , vasodilation , arginine , pharmacodynamics , impedance cardiography , medicine , vascular resistance , excretion , blood pressure , oral administration , pharmacology , endocrinology , chemistry , heart rate , biochemistry , amino acid , stroke volume
Aims Administration of l‐arginine by intravenous infusion or via oral absorption has been shown to induce peripheral vasodilation in humans, and to improve endothelium‐dependent vasodilation. We investigated the pharmacokinetics and pharmacokinetic‐pharmacodynamic relationship of l‐arginine after a single intravenous infusion of 30 g or 6 g, or after a single oral application of 6 g, as compared with the respective placebo, in eight healthy male human subjects.Methods l‐arginine levels were determined by h.p.l.c. The vasodilator effects of l‐arginine were assessed non‐invasively by blood pressure monitoring and impedance cardiography. Urinary nitrate and cyclic GMP excretion rates were measured as non‐invasive indicators of endogenous NO production.Results Plasma l‐arginine levels increased to (mean±s.e.mean) 6223±407 (range, 5100–7680) and 822±59 (527–955) μmol l −1 after intravenous infusion of 30 g and 6 g l‐arginine, respectively, and to 310±152 (118–1219) μmol l −1 after oral ingestion of 6 g l‐arginine. Oral bioavailability of l‐arginine was 68±9 (51–87)%. Clearance was 544±24 (440–620), 894±164 (470–1190), and 1018±230 (710–2130) ml min −1 , and elimination half‐life was calculated as 41.6±2.3 (34–55), 59.6±9.1 (24–98), and 79.5±9.3 (50–121) min, respectively, for 30 g i.v., 6 g i.v., and 6 g p.o. of l‐arginine. Blood pressure and total peripheral resistance were significantly decreased after intravenous infusion of 30 g l‐arginine by 4.4±1.4% and 10.4±3.6%, respectively, but were not significantly changed after oral or intravenous administration of 6 g l‐arginine. l‐arginine (30 g) also significantly increased urinary nitrate and cyclic GMP excretion rates by 97±28 and 66±20%, respectively. After infusion of 6 g l‐arginine, urinary nitrate excretion also significantly increased, (nitrate by 47±12% [P<0.05], cyclic GMP by 67±47% [P =ns]), although to a lesser and more variable extent than after 30 g of l‐arginine. The onset and the duration of the vasodilator effect of l‐arginine and its effects on endogenous NO production closely corresponded to the plasma concentration half‐life of l‐arginine, as indicated by an equilibration half‐life of 6±2 (3.7–8.4) min between plasma concentration and effect in pharmacokinetic‐pharmacodynamic analysis, and the lack of hysteresis in the plasma concentration‐versus‐effect plot.Conclusions The vascular effects of l‐arginine are closely correlated with its plasma concentrations. These data may provide a basis for the utilization of l‐arginine in cardiovascular diseases.