Bousquet E, Marrazzo A, Puglisi G, Spadaro A, Tirendi S
Istituto di Chimica Farmaceutica e Tossicologica, Università di Catania, Italy.
J Pharm Pharmacol. 1996 May;48(5):479-85. doi: 10.1111/j.2042-7158.1996.tb05958.x.
Paracetamol ester prodrugs with L-pyroglutamic and L-glutamic acid, biosynthetic precursors of glutathione, have been synthesized to reduce paracetamol hepatotoxicity and improve bioavailability. The toxicological studies of paracetamol esters show that only L-5-oxo-pyrrolidine-2-paracetamol carboxylate reduces toxicity after administration of an overdose. The glutathione hepatic values in mice obtained by intraperitoneal injection of the ester are superimposable on controls and the oral LD50 was found to be greater than 2000 mg kg-1 and the intraperitoneal LD50 was 1900 mg kg-1. These results taken together with hydrolysis and bioavailability data show that ester is a potential candidate as a prodrug of paracetamol.
已合成了与谷胱甘肽的生物合成前体L-焦谷氨酸和L-谷氨酸形成的对乙酰氨基酚酯前药，以降低对乙酰氨基酚的肝毒性并提高生物利用度。对乙酰氨基酚酯的毒理学研究表明，仅L-5-氧代吡咯烷-2-对乙酰氨基酚羧酸盐在过量给药后可降低毒性。通过腹腔注射该酯获得的小鼠肝脏谷胱甘肽值与对照组相当，口服半数致死量（LD50）大于2000 mg/kg，腹腔注射LD50为1900 mg/kg。这些结果与水解和生物利用度数据一起表明，该酯是对乙酰氨基酚前药的潜在候选物。
