Pharmacokinetics of intravenous and oral L‐arginine in normal volunteers

Tangphao, Oranee; Großmann, Matthias; Chalon, Stephan; Hoffman, Brian B.; Blaschke, Terrence F.

doi:10.1046/j.1365-2125.1999.00883.x

Cited by 98 publications

(84 citation statements)

References 30 publications

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“…The plasma arginine concentration reached peak at 60 minutes, and then gradually decreased after oral arginine administration. This change in the plasma concentration of arginine is consistent with other reports 14,15) . Therefore, there is a possibility that the expression of airway epithelial NOS is higher in the subjects with history of allergy.…”

Section: Discussionsupporting

confidence: 93%

Effect of Oral L-Arginine Administration on Exhaled Nitric Oxide (No) Concentration in Healthy Volunteers

Ogata

Yatabe

Misaka

et al. 2013

FJMS

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: We previously reported a case of pulmonary hypertension, where the symptoms were improved by oral L -arginine (arginine) administration. Arginine may increase nitric oxide (NO) production in the pulmonary artery. Exhaled NO may reflect pulmonary artery NO production. It has been demonstrated that exhaled NO concentration is higher in patients with allergic diseases, but whether oral arginine administration alters exhaled NO is unknown. Therefore, in this study, we investigated whether oral arginine administration increases exhaled NO among healthy volunteers with and without a history of allergy. Eleven subjects were given a single oral dose (200 mg/kg) of arginine, and their plasma arginine concentrations and exhaled NO were measured up to 150 minutes. Baseline values of exhaled NO concentration were significantly higher in those with a history of allergy (56.4±20.3 ppb, n=5, P<0.05) than those without (16.8±4.0 ppb, n=6). Oral arginine increased exhaled NO, which peaked at 60 minutes after the administration in those with a history of allergy (85.2±44.8 ppb, n=5). However, the increase in exhaled NO was not significant compared to the baseline values. In contrast, plasma arginine concentration was increased significantly by arginine administration (P<0.01), regardless of an allergy history. These results suggested that the difference in exhaled NO concentration was not due to a difference in arginine absorption. Serum IgE level was significantly higher in the group with a history of allergy. Eosinophils and white blood cells were within normal range in all subjects. We conclude that oral arginine administration does not significantly increase exhaled NO, regardless of allergy history. However, as arginine administration has been reported to be effective in patients with pulmonary hypertension, it will be necessary to test exhaled NO in subjects with pulmonary hypertension in the future.

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Section: Discussionsupporting

confidence: 93%

Effect of Oral L-Arginine Administration on Exhaled Nitric Oxide (No) Concentration in Healthy Volunteers

Ogata

Yatabe

Misaka

et al. 2013

FJMS

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“…Early L-arginine pharmacokinetic studies (22,27) were limited by short sampling periods and insensitive enzymatic and photometric assays with high coefficients of variation. Morerecent studies have examined the pharmacokinetics after infusions of 6 g and 30 g of L-arginine over 30 min into healthy volunteers (4,13,25). After a 6 g infusion, the mean peak L-arginine concentration in plasma of 822 mol/liter (4) was comparable to the mean peak concentration of 809 mol/liter for patients with malaria.…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest that rapid turnover of L-arginine occurs in patients with acute inflammatory states, although there are no pharmacokinetic data available for ill subjects. Previously published studies of L-arginine pharmacokinetics have been done with healthy volunteers (4,22,25,27), in whom L-arginine metabolism is likely to differ significantly from that in acutely ill individuals. Early L-arginine pharmacokinetic studies (22,27) were limited by short sampling periods and insensitive enzymatic and photometric assays with high coefficients of variation.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of l -Arginine in Adults with Moderately Severe Malaria

Yeo

Rooslamiati

Gitawati

et al. 2008

Antimicrob Agents Chemother

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Severe malaria is associated with decreased nitric oxide (NO) production and low plasma concentrations of L-arginine, the substrate for NO synthase. Supplementation with L-arginine has the potential to improve NO bioavailability and outcomes. We developed a pharmacokinetic model for L-arginine in moderately severe malaria to explore the concentration-time profile and identify important covariates. In doses of 3, 6, or 12 g, L-arginine was infused over 30 min to 30 adults with moderately severe malaria, and plasma concentrations were measured at 8 to 11 time points. Patients who had not received L-arginine were also assessed and included in the model. The data were analyzed using a population approach with NONMEM software. A two-compartment linear model with first-order elimination best described the data, with a clearance of 44 liters/h (coefficient of variation [CV] ‫؍‬ 52%) and a volume of distribution of 24 liters (CV ‫؍‬ 19%). The natural time course of L-arginine recovery was described empirically by a second-order polynomial with a time to half recovery of 26 h. The half-life of exogenous L-arginine was reduced in patients with malaria compared with that for healthy adults. Weight and ethnicity were significant covariates for clearance. MATLAB simulations of dosing schedules for use in future studies predicted that 12 g given over 6, 8, or 12 h will provide concentrations above the K m of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively.The treatment of severe malaria currently relies on antimalarial drugs and supportive treatments, but the early case fatality rate remains high (8). Adjunctive therapies targeting underlying pathogenic processes early in the treatment of severe malaria may reduce mortality further, but to date none have proven efficacious (10). L-Arginine has been proposed as a potential adjunctive therapy for severe malaria because of its ability to increase nitric oxide (NO) production in endothelial and other cells (16, 34).We have previously described impaired production of NO (1, 34); low plasma concentrations of its precursor, L-arginine (16); and impaired NO-dependent endothelial function in cases of severe malaria (34). Endothelial dysfunction is a measure of endothelial activation and may play a role in the pathogenesis of severe malaria by increasing the adhesion of parasitized erythrocytes to the endothelium and thereby worsening microcirculatory obstruction and oxygen delivery (9). NO downregulates endothelial inflammation (7) and reduces the cytoadherence of parasitized erythrocytes in vitro (20,23). Endothelial NO production is dependent on the intracellular movement of extracellular L-arginine by cationic amino acid transporter protein-1 (CAT-1) (35). Estimates for the halfsaturating concentration (K m ) of extracellular L-arginine for CAT-1 are 100 to 150 mol/liter (32), within the estimated range of the K m of extracellular L-arginine for intracellular NO production (73 to 150 mol/liter) (11, 14). In severe malaria, plasma L-arginine concen...

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“…The inducible form of NO synthase protein increased in an L-arg-dependent manner, which resulted in the killing of H. pylori. The average baseline plasma concentration of L-arg in healthy subjects is 60-100 M (30,31). This value increases until 300 M after a single oral administration of a 10-g dose with bioavailbility of ϳ20% and until 6.6 mM after intravenous administration of a 30-g dose (30,31).…”

Section: Resultsmentioning

confidence: 99%