In vivo studies on toxic effects of concurrent administration of paracetamol and its N-acetyl-DL-methionine ester (SUR 2647 combination).
1. Single p.o. doses of paracetamol 400 and 800 mg/kg or SUR 2647 combination (free paracetamol + paracetamol-N-acetyl-DL-methionate, paracetamol/methionine ratio 2:1) equivalent to paracetamol 400 and 800 mg/kg were given to Bom:NMRI mice. Vehicle treated (1% w/v aqueous methylcellulose) mice were established as a control group. 2. All treatment groups irrespective of medication caused an initial GSH depletion. However, SUR 2647 combination 400 mg/kg caused a much earlier hepatic GSH recovery than paracetamol 400 mg/kg. SUR 2647 combination 800 mg/kg caused a higher hepatic GSH level than paracetamol 800 mg/kg. 3. There was no significant difference in the plasma ALAT level after SUR 2647 combination 400 or 800 mg/kg and the control group. Paracetamol 400 and 800 mg/kg caused significant plasma ALAT elevations compared to the control group. 4. The addition of N-acetyl-DL-methionine esterified to paracetamol, as in the SUR 2647 combination, enhances the hepatic GSH synthesizing capacity in Bom:NMRI mice after experimental overdosage and offers protection of hepatic cell integrity as assessed by plasma ALAT level compared to paracetamol alone.
Skoglund
L A
LA
Department of Pharmacology and Toxicology, Norwegian College of Veterinary Medicine, Oslo.
Ingebrigtsen
K
K
Nafstad
I
I
Aalen
O
O
D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000622:Aminolevulinic Acid / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice
D000082:Acetaminophen; C042733:SUR 2647; D000622:Aminolevulinic Acid; D000410:Alanine Transaminase; D005978:Glutathione