Price V F, Jollow D J
Drug Metab Dispos. 1983 Sep-Oct;11(5):451-7.
The effects of ketones on acetaminophen metabolism and hepatotoxicity were investigated in male rats. Ketosis was produced by oral administration of either acetone or 1,3-butanediol. Histologic studies revealed that both ketogenic agents conferred protection from acetaminophen-induced liver necrosis. Pharmacokinetic studies indicated that both acetone and 1,3-butanediol: a) increased the blood half-life of acetaminophen, b) markedly decreased the apparent rate constant for formation of acetaminophen mercapturate, and c) modestly decreased the capacities for acetaminophen sulfate formation and renal elimination of the drug. Neither acetone nor 1,3-butanediol had any effect on either the apparent rate constant for formation of acetaminophen glucuronide or on the predrug levels of hepatic glutathione. However, after a large dose of acetaminophen, the rate and percentage of glutathione depletion were markedly less in 1,3-butanediol-treated rats and modestly less in acetone-treated rats as compared with controls. These data indicate that acetone- or 1,3-butanediol-induced ketosis confers protection from hepatic necrosis due largely to decreased formation of the reactive metabolite. The effects of ketosis and of diabetes on acetaminophen metabolism and hepatotoxicity are compared.
在雄性大鼠中研究了酮类对乙酰氨基酚代谢及肝毒性的影响。通过口服丙酮或1,3 - 丁二醇诱导产生酮血症。组织学研究表明，两种生酮剂均可对乙酰氨基酚诱导的肝坏死起到保护作用。药代动力学研究表明，丙酮和1,3 - 丁二醇均：a）延长了乙酰氨基酚的血液半衰期，b）显著降低了乙酰氨基酚巯基尿酸盐形成的表观速率常数，c）适度降低了乙酰氨基酚硫酸盐形成能力及药物的肾排泄。丙酮和1,3 - 丁二醇对乙酰氨基酚葡糖醛酸苷形成的表观速率常数或肝谷胱甘肽的给药前水平均无任何影响。然而，与对照组相比，在给予大剂量乙酰氨基酚后，1,3 - 丁二醇处理的大鼠中谷胱甘肽耗竭的速率和百分比显著降低，丙酮处理的大鼠中谷胱甘肽耗竭的速率和百分比适度降低。这些数据表明，丙酮或1,3 - 丁二醇诱导的酮血症主要通过减少活性代谢物的形成而对肝坏死起到保护作用。比较了酮血症和糖尿病对乙酰氨基酚代谢及肝毒性的影响。
