Aminopyrine disposition: A sensitive index of acetaminophen-induced hepatocellular damage☆

Abstract Rates of 14 CO 2 excretion in breath and of plasma decay of [ 14 C]aminopyrine were measured after intraperitoneal administration of trace doses of [ 14 C]aminopyrine in adult male Wistar rats: Both measurements were shown to be sensitive indices of hepatic aminopyrine N -demethylation. Thus, changes in the disposition of aminopyrine administered ip could be used to investigate effects of different doses of acetaminophen on hepatic drug-metabolizing capacity. After the administration of different doses of acetaminophen, liver damage was assessed by measurement of glutathione content, cytochrome P -450 content, and microsomal demethylation capacity as well as by liver histology. Decreased 14 CO 2 excretion, suggesting decreased hepatic aminopyrine N -demethylase activity, occurred even in animals with minimal acetaminophen-induced hepatic injury. Further reduction of 14 CO 2 excretion occurred with increasing doses of acetaminophen, which caused more extensive liver damage. These results suggest that measurement of 14 CO 2 accumulation in breath can serve as a convenient, sensitive, and noninvasive laboratory test to assess in vivo hepatic drug-metabolizing capacity under a variety of conditions, including liver damage secondary to exposure to toxic compounds.