Acetaminophen hepatotoxicity is believed to result from the metabolic conversion of acetaminophen to a highly reactive intermediate by cytochrome P450. Cimetidine has been shown to be a potent inhibitor of cytochrome P450-mediated drug metabolism in humans and in laboratory animals, both in vivo and in vitro. Therefore, this study was undertaken to examine the possible protective effects of cimetidine administration on acetaminophen-induced hepatic necrosis in rats. We observed a striking protection against acetaminophen hepatotoxicity in cimetidine-treated animals had less histologic damage when examined by light microscopy, and they had lower serum aminotransferase than those treated with acetaminophen alone. Furthermore, there was less functional hepatic impairment, e.g., improved survival and improved ability to metabolize aminopyrine in vivo in rats receiving cimetidine compared with those receiving acetaminophen without cimetidine. Comparison of cimetidine treatment with N-acetylcysteine treatment of acetaminophen overdose in rats showed cimetidine as effective as N-acetylcysteine, even though the dose of cimetidine given was only 1/15 th that of N-acetylcysteine on a molar basis. Cimetidine also inhibited the covalent binding of [3H]acetaminophen to hepatic microsomes in vitro, both in the presence and absence of reduced glutathione. Cimetidine did not, however, increase total hepatic glutathione stores within 4 h of its i.p. administration. Thus, we have shown that cimetidine effectively reduces acetaminophen hepatotoxicity in rats. Although the exact mechanism of its protective action is unproven, it seems likely that cimetidine inhibits the formation of the reactive metabolite of acetaminophen both in vivo and in vitro.
|Original language||English (US)|
|Number of pages||9|
|State||Published - 1981|
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