Background:Preterm neonates are exposed to a relatively high oxygen pressure resulting in formation of reactive oxygen species, which may lead to the development of chronic lung disease and retinopathy. The synthesis of glutathione, a major intracellular antioxidant, may not be adequate in preterm neonates because of the low levels of cysteine available. N-acetylcysteine (NAC) is both a free radical scavenger and a precursor for cysteine. It has been suggested to increase glutathione synthesis.

Objective:To investigate the pharmacokinetics of NAC in preterm neonates in order to find a proper dosage for further prevention trials.

Methods:Newborn infants requiring assisted ventilation (BW 500-1384g, GA 24-31 weeks) were enrolled. In the first study, n=10, NAC infusion was started soon after birth (range 2-6h) at a constant rate of 100 mg/kg/d for 24h. In the second study, n=6, the NAC-infusion, at a constant rate of 10-24mg/kg/d, was started at the age of 24h and lasted for 6 days. The dosage was based on results obtained in the first study and aimed at a steady-state plasma NAC concentration of 100μmol/l. The smallest infants received the lowest doses. NAC concentration was measured from arterial plasma with an HPLC method with fluorometric detection.

Results:In the first study, the plasma concentrations of NAC increased up to the end of the infusion in 9 out of 10 infants, i.e. the steady-state concentration was not fully reached. At the end of the infusion, the mean plasma concentration of NAC was 511μmol/l (range 381-766). When the infusion was discontinued, NAC disappeared from the plasma with a mean elimination half-life of 11h (range 8-15). The plasma clearance (range 13-56ml/kg/h) and the volume of distribution (range 160-1010ml/kg) correlated well with weight (r=0.81,p<0.01 and r=0.78,p<0.01, respectively) and with gestational age (r=0.71,p<0.05 and r=0.64,p<0.05 respectively), whereas the elimination half-life did not. In the second study, the steady-state concentration of plasma NAC was reached in 5 of 6 patients within 50-70 h. The infusion rate and the steady-state concentration of NAC correlated significantly (R=1.0, p<0.001).

Conclusions:In preterm neonates, NAC is eliminated slowly, with a mean half-life of 11 hours, which is clearly longer than described for adults. The clearance correlates well with weight and gestational age. In most of the patients, a steady-state concentration was reached within 2-3 days, at a constant infusion rate of NAC.