Influence of ascorbic acid esters on acetaminophen-induced hepatotoxicity in mice.
Groups of male Swiss-Webster mice were gavaged with acetaminophen (APAP), APAP + ascorbyl stearate (AS), or APAP + ascorbyl palmitate (AP) at a dose of 600 mg/kg for each chemical. APAP alone caused a significant increase in liver weight/body weight ratio and hepatic glutathione (GSH) depletion. Co-administration of the ascorbate esters AP or AS with APAP prevented an increase in liver weight/body weight ratios and hepatic glutathione depletion. APAP + AS treatments caused significantly greater reductions in rectal temperature at 15-30 min post-dosing periods when compared to APAP + AP or AS treatments. Blood levels of APAP had the same relationship. The study indicates a correlation between APAP blood levels and antipyretic effect of APAP + AS and APAP + AP coadministrations. While both ascorbate esters probably afford protection against APAP-induced hepatotoxicity in mice by reducing the reactive intermediate back to the parent compound, the APAP + AS combination provides better therapeutic efficacy as an antipyretic at the 15-30 min post-dosing periods.
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Division of Pharmacology and Toxicology, School of Pharmacy, Northeast Louisiana University, Monroe 71209.
Ravikumar
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Bourn
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Bourcier
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D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000097:blood / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D004359:Drug Therapy, Combination; D005334:Fever / Q000188:drug therapy; D005978:Glutathione / Q000032:analysis; D008099:Liver / Q000032:analysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen; C036225:ascorbyl monostearate; D005978:Glutathione; D001205:Ascorbic Acid; C031226:6-O-palmitoylascorbic acid