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Distribution and metabolism of N(G)-nitro-L-arginine methyl ester in patients with septic shock.

Abstract：

OBJECTIVE:The pharmacokinetics of N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, was investigated in patients with septic shock. METHODS:Blood was sampled at intervals before, during and after 12-h infusion of L-NAME 1 mg x kg(-1) x h(-1) in nine septic shock patients for determination of plasma concentrations by high-performance liquid chromatography (HPLC). In three patients the renal clearance of the drug was determined. RESULTS:Incubation of L-NAME with plasma and blood in vitro revealed hydrolysis to N(G)-nitro-L-arginine (L-NOARG), the active inhibitor of NO synthesis. L-NOARG did not undergo further degradation. Continuous intravenous infusion of 1 mg x kg(-1) x h(-1) of L-NAME for 12 h in patients with septic shock increased blood pressure and resulted in increasing plasma concentrations of L-NOARG (Cmax 6.2 microg x ml(-1) at 12 h) whereas L-NAME concentrations reached a plateau within 1.5 h (Cmax 1.0 microg x ml(-1)). After the infusion was stopped L-NAME disappeared from the plasma rapidly (half-life 19.2 min) whereas L-NOARG concentration declined slowly (half-life 22.9 h). The calculated volume of distribution for L-NAME was 0.451 x kg(-1) body weight and 1.961 x kg(-1) for L-NOARG. The renal clearance for L-NOARG was 3.5% of total body clearance for L-NOARG, whereas L-NAME could not be detected in urine. CONCLUSION:We conclude that vasoconstriction with L-NAME in septic patients may result from hydrolysis to L-NOARG, the active inhibitor of NO synthesis. The long plasma half-life and large volume of distribution for L-NOARG suggests extensive distribution to extravascular tissues. Since renal excretion is minimal, elimination of the metabolite L-NOARG follows other pathways.

journal_name

Eur J Clin Pharmacol

journal_title

European journal of clinical pharmacology

authors

Avontuur JA,Buijk SL,Bruining HA

doi

10.1007/s002280050525

subject

Has Abstract

pub_date

1998-10-01 00:00:00

pages

627-31

issue

8

eissn

0031-6970

issn

1432-1041

journal_volume

54

pub_type

临床试验,杂志文章

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