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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