Bode-Böger S M, Böger R H, Galland A, Tsikas D, Frölich J C
Institute of Clinical Pharmacology, Medical School, Hannover, Germany.
Br J Clin Pharmacol. 1998 Nov;46(5):489-97. doi: 10.1046/j.1365-2125.1998.00803.x.
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.
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.
Plasma L-arginine levels increased to (mean +/- s.e.mean) 6223+/-407 (range, 5100-7680) and 822+/-59 (527-955) micromol l(-1) after intravenous infusion of 30 g and 6 g L-arginine, respectively, and to 310+/-152 (118-1219) micromol 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.
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.
静脉输注或口服吸收L-精氨酸已被证明可诱导人体外周血管舒张，并改善内皮依赖性血管舒张。我们在8名健康男性受试者中，比较了单次静脉输注30 g或6 g L-精氨酸、单次口服6 g L-精氨酸与相应安慰剂后，L-精氨酸的药代动力学及药代动力学-药效学关系。
采用高效液相色谱法测定L-精氨酸水平。通过血压监测和阻抗心动图非侵入性评估L-精氨酸的血管舒张作用。测定尿硝酸盐和环磷酸鸟苷排泄率，作为内源性一氧化氮生成的非侵入性指标。
静脉输注30 g和6 g L-精氨酸后，血浆L-精氨酸水平分别升至（均值±标准误）6223±407（范围5100 - 7680）和822±59（527 - 955）μmol/L，口服6 g L-精氨酸后升至310±152（118 - 1219）μmol/L。L-精氨酸的口服生物利用度为68±9（51 - 87）%。清除率分别为544±24（440 - 620）、894±164（470 - 1190）和1018±230（710 - 2130）ml/min，30 g静脉注射、6 g静脉注射和6 g口服L-精氨酸的消除半衰期分别计算为41.6±2.3（34 - 55）、59.6±9.1（24 - 98）和79.5±9.3（50 - 121）分钟。静脉输注30 g L-精氨酸后，血压和总外周阻力分别显著降低4.4±1.4%和10.4±3.6%，但口服或静脉注射6 g L-精氨酸后无显著变化。L-精氨酸（30 g）还使尿硝酸盐和环磷酸鸟苷排泄率分别显著增加97±28%和66±20%。输注6 g L-精氨酸后，尿硝酸盐排泄也显著增加（硝酸盐增加47±12%[P<0.05]，环磷酸鸟苷增加67±47%[P=无显著性差异]），尽管程度小于30 g L-精氨酸且变化更大。L-精氨酸血管舒张作用的起效和持续时间及其对内源性一氧化氮生成的影响与L-精氨酸的血浆浓度半衰期密切相关，药代动力学-药效学分析显示血浆浓度与效应之间的平衡半衰期为6±2（3.7 - 8.4）分钟，且血浆浓度-效应图中无滞后现象。
L-精氨酸的血管效应与其血浆浓度密切相关。这些数据可为L-精氨酸在心血管疾病中的应用提供依据。
