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, 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.
Bousquet
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E
Istituto di Chimica Farmaceutica e Tossicologica, Università di Catania, Italy.
Marrazzo
A
A
Puglisi
G
G
Spadaro
A
A
Tirendi
S
S
D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D005971:Glutamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D006868:Hydrolysis; D007928:Lethal Dose 50; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D011817:Rabbits
D005971:Glutamates; D011355:Prodrugs; D000082:Acetaminophen; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid