Distribution and metabolism of NG-nitro-L-arginine methyl ester in patients with septic shock

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 . kg(-1) . h(-1) in nine septic shock patients for determination of plasma concentrations hv high-performance liquid chromatography (HPLC). Tn 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 . kg(-1) . 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 (C-max 6.2 mu g . ml(-1) at 12 h) whereas L-NAME concentrations reached a plateau within 1.5 h (C-max 1.0 mu g . 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 0.45 l . kg(-1) body weight and 1.96 l . 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.