Pharmacokinetics of intravenous N-acetylcysteine in men at rest and during exercise

Abstract

Objective: We aimed to determine the pharmacokinetics (PK) of N-acetylcysteine (NAC) at rest and during exercise when given by continuous intravenous infusion intended to maintain relatively constant plasma concentrations. Methods: Plasma concentrations of NAC were measured in 24 healthy male subjects during and after a two-stage intravenous infusion designed to provide constant NAC concentrations during cycling exercise, including intense exercise to fatigue. Results: A three-compartment, open PK model was the best fit using population PK analysis with NONMEM. Whole-body clearance (CL) was 0.58 l kg⁻¹ h⁻¹ (95% CI 0.44–0.72) for reduced NAC (NACR) and 0.16 (0.13–0.20) l kg⁻¹ h⁻¹ for total NAC (NACT). The central volume of distribution (V1) was 0.064 (0.008–0.12) l kg⁻¹ for NACR and 0.037 (0.02–0.06) l kg⁻¹ for NACT. Exercise was a significant covariate in the model, resulting in a 25 and 23% reduction in CL of NACR and NACT, respectively. V1 in our subjects was smaller than expected, resulting in higher-than-anticipated initial concentrations of NAC. Despite these findings, the incidence of adverse effects attributable to NAC was minimal without using prophylactic or concomitant drug therapy. Conclusions: NAC can be given to healthy exercising men by intravenous infusion and to the plasma concentrations seen in this study with minimal adverse effects due to the drug. The PK parameters of NAC at rest in volunteers are consistent with previously reported values and are significantly altered by vigorous cycling exercise.