SYNTHESIS, PHYSICAL-PROPERTIES, TOXICOLOGICAL STUDIES AND BIOAVAILABILITY OF L-PYROGLUTAMIC AND L-GLUTAMIC ACID-ESTERS OF PARACETAMOL AS POTENTIALLY USEFUL PRODRUGS

Paracetamol ester prodrugs with L-pyroglutamic and L-glutamic acid, bi osynthetic precursors of glutathione, have been synthesized to reduce paracetamol hepatotoxicity and improve bioavailability. The toxicologi cal studies of paracetamol esters show that only L-5-oxo-pyrrolidipe-2 -paracetamol carboxylate reduces toxicity after administration of an o verdose. The glutathione hepatic values in mice obtained by intraperit oneal injection of the ester are superimposable on controls and the or al LD50 was found to be greater than 2000 mg kg(-1) and the intraperit oneal LD50 was 1900 mg kg(-1). These results taken together with hydro lysis and bioavailability data show that ester is a potential candidat e as a prodrug of paracetamol.