Acute administration of L-arginine, the precursor of endothelial nitric oxide, has been shown to improve endothelial function in hypercholesterolaemic rabbits and humans. Animal studies suggest that this beneficial effect, which is thought to be related to the increased availability of nitric oxide, may not be sustained during chronic oral administration. Pharmacokinetic alterations may contribute to this observation. The present study was designed to examine the disposition of L-arginine in hypercholesterolaemic subjects during long-term administration. Plasma L-arginine concentrations were determined by HPLC in 10 patients (eight women and two men; mean age 46±16 years) after an intravenous dose of 10 or 30 g and an oral dose of 5 or 7 g. Pharmacokinetic studies were performed at regular intervals (4 weeks) during a 12-week period of oral L-arginine administration (14–21 g/day). The average plasma L-arginine concentrations before (baseline) and during administration were 16.1±1.2 and 22.5±1.3 μg/ml respectively (P< 0.05). Plasma concentrations of L-arginine remained above baseline throughout weeks 2–12. The L-arginine exposure, expressed as a normalized area-under-the-curve for 8 h (AUC0–8) after oral or intravenous doses during the first visit, was 894.4±118.7 and 1837.8±157.0 units respectively. There were no significant changes in peak plasma L-arginine concentrations or in the AUC0–8 after oral and intravenous doses during subsequent visits (P> 0.05). The mean non-renal clearance of L-arginine during the four visits remained constant. Knowledge of the pharmacokinetics of L-arginine may be useful in the design of clinical trials involving this agent, as well as in the interpretation of the pharmacodynamics of this important precursor of nitric oxide.

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