Protective effect of stiripentol on acetaminophen-induced hepatotoxicity in rat.
Acetaminophen (APAP) is mainly eliminated at a therapeutic dose through glucuronidation and sulfatation and a small fraction is oxidized by cytochromes P450 (CYP) 2E1, 3A4, and 1A2 to N-acetyl-p-benzoquinone-imine (NAPQI), a highly reactive metabolite further conjugated with glutathione into APAP-GSH, and then metabolized to APAP-cystein and APAP-mercapturate excreted in urine. After APAP overdose, the glucuronidation and sulfatation pathways are saturated and the production of NAPQI increases, causing hepatic injury. Stiripentol (STP); (200 mg/kg), an anticonvulsant drug inhibitor of CYP1A2 and CYP3A4 in vivo in humans was tested against APAP-induced toxicity in rat in comparison with N-acetylcysteine (NAC; 100 mg/kg). The mortality rates 24 h after APAP overdose (2 x 500 mg/kg) were 63% (control), 38% (NAC), 0% (STP), and 4% (STP + NAC). The mean plasma transaminase concentrations 5 and 24 h after overdose were significantly higher in control than in STP and NAC groups. The percentage of rats without microscopic liver necrosis 5 h after APAP overdose was significantly higher in rats receiving STP (100%), NAC (83%), or STP + NAC (83%) than controls (42%). In another experiment, four similar groups were administered 50 mg/kg APAP. Plasma AUC(0-5 h) for APAP-GSH, APAP-cystein, and APAP-mercapturate as well as urine APAP-mercapturate mean amounts were significantly lower in STP animals than in the other groups. STP (200 mg/kg) inhibited NAPQI synthesis through CYP inhibition, thus preventing both liver necrosis and mortality in rats.
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Service de Pharmacologie Périnatale et Pédiatrique, Hôpital Saint-Vincent de Paul, Faculté de Médecine Cochin Port-Royal--Université René Descartes, Paris, France.
Tréluyer
J M
JM
Rey
E
E
Barbet
J
J
Ferracci
G
G
d'Athis
P
P
Vincent
J
J
Pons
G
G
D000082:Acetaminophen / Q000097:blood / Q000633:toxicity / Q000652:urine; D000111:Acetylcysteine / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D004148:Dioxolanes / Q000494:pharmacology*; D004338:Drug Combinations; D062787:Drug Overdose; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004148:Dioxolanes; D004338:Drug Combinations; D000082:Acetaminophen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C021092:stiripentol; D000111:Acetylcysteine