Efficacy of paracetamol-esterified methionine versus cysteine or methionine on paracetamol-induced hepatic GSH depletion and plasma ALAT level in mice.

The effect of paracetamol-N-acetyl-DL-methionate (PAM) in preventing paracetamol-induced hepatic glutathione (GSH) depletion and hepatic cell damage assessed by plasma ALAT level, was compared to those of concomitantly administered paracetamol and N-acetyl-L-cysteine (NAC) or N-acetyl-DL-methionine (NAM) and paracetamol 400 mg/kg (P) alone. PAM, NAM and NAC reduced hepatic GSH depletion compared to P. The concomitant administration of GSH precursors in either form apparently maintained hepatic cell integrity as evaluated by plasma ALAT compared to predose and 16 hr control measurements. No statistically significant difference between PAM, NAM and NAC was observed. In group P a statistically significant, but transitory, rise in plasma ALAT level following dosage was seen. NAC was more effective than PAM and NAM in the prevention of GSH depletion 1 hr after dosing but was less effective in promoting de novo GSH synthesis towards 16 hr. There was no statistically significant difference between PAM and NAM with respect to effect on GSH depletion or hepatic cell integrity. PAM and NAM increased the GSH level significantly above control level 16 hr after dosing. PAM is rapidly cleaved to paracetamol and methionine following dosage as shown by the observed plasma paracetamol level. PAM compares favourably in hepatoprophylactic effect, to concomitant administration of equimolar doses of free N-acetyl-DL-methionine added to the paracetamol formulation.