Chan Wei-Hung, Sun Wei-Zen, Ueng Tzuu-Huei
Institute of Toxicology, National Taiwan University, Taipei, Taiwan.
J Toxicol Environ Health A. 2005 Sep;68(17-18):1581-97. doi: 10.1080/15287390590967522.
Ketamine is a common intravenous anesthetic and a frequent drug of abuse, alone or in combination with cocaine. However, the pharmacokinetic effects of ketamine have not been fully investigated. This study determined the effects of ketamine on cytochrome P-450 (P-450)-dependent catalytic activities, protein levels, and hepatotoxicity using male Wistar rats treated with 10, 20, 40, or 80 mg/kg ketamine intraperitoneally twice daily for 4 d. Treatment with ketamine produced a dose-dependent increase of pentoxyresorufin O-dealkylation activity of liver microsomes. Treatment with 80 mg/kg ketamine resulted in 14-, 3-, and 2-fold rise in O-dealkylation of pentoxyresorufin, ethoxyresorufin, and methoxyresorufin of rat liver microsomes, respectively. The treatment produced 31% and 86% increases in 7-ethoxycoumarin O-deethylation and erythromycin N-demethylation, respectively. In addition, aniline hydroxylation activity was elevated by 62%. Protein blot analysis of liver microsomal proteins revealed that 80 mg/kg ketamine induced P-450 1A, 2B, 2E1, and 3A proteins by 2-, 13-, 2-, and 2-fold, respectively. In reversibility study, ketamine-induced pentoxyresorufin O-dealkylation, 7-ethoxycoumarin O-deethylation, erythromycin N-demethylation, and methoxyresorufin O-demethylation activities of liver microsomes prepared from rats 4 d after ketamine treatment were 75%, 48%, 29%, and 38% lower than the respective activities of liver microsomes prepared from rats 1 d after treatment. Protein blot analysis showed that ketamine-induced P-450 2B1/2 proteins also decreased in a time-dependent manner in 4 d. In hepatotoxicity study, treatment of rats with 1 ml/kg CCl4 produced a 7-fold increase in serum alanine aminotransferase activity level and a 17-fold rise in rats pretreated with 80 mg/kg ketamine for 4 d. Treatment of ICR mice with 120 mg/kg cocaine produced a 17% mortality, whereas the same dose of cocaine produced a 50% mortality in mice pretreated with ketamine. Treatment of mice with 100 mg/kg cocaine produced a 76-fold increase in serum alanine aminotransferase activity level and a 260-fold rise in mice pretreated with 80 mg/kg ketamine for 4 d. The present study shows that ketamine induces the expression of multiple forms of P-450 in rat liver microsomes and increases CCl4-induced liver toxicity and cocaine-mediated acute toxicity. Other potential pharmacological or toxicological events related to ketamine use need to be further explored.
氯胺酮是一种常见的静脉麻醉剂，也是一种经常被滥用的药物，单独使用或与可卡因混合使用。然而，氯胺酮的药代动力学效应尚未得到充分研究。本研究使用雄性Wistar大鼠，每天腹腔注射10、20、40或80mg/kg氯胺酮，连续4天，以确定氯胺酮对细胞色素P-450（P-450）依赖性催化活性、蛋白质水平和肝毒性的影响。氯胺酮治疗导致肝微粒体戊氧基试卤灵O-脱烷基化活性呈剂量依赖性增加。用80mg/kg氯胺酮治疗导致大鼠肝微粒体中戊氧基试卤灵、乙氧基试卤灵和甲氧基试卤灵的O-脱烷基化分别升高14倍、3倍和2倍。该治疗分别使7-乙氧基香豆素O-脱乙基化和红霉素N-脱甲基化增加31%和86%。此外，苯胺羟化活性提高了62%。肝微粒体蛋白的蛋白质印迹分析显示，80mg/kg氯胺酮分别使P-450 1A、2B、2E1和3A蛋白诱导增加2倍、13倍、2倍和2倍。在可逆性研究中，氯胺酮治疗4天后大鼠制备的肝微粒体中，氯胺酮诱导的戊氧基试卤灵O-脱烷基化、7-乙氧基香豆素O-脱乙基化、红霉素N-脱甲基化和甲氧基试卤灵O-脱甲基化活性分别比治疗1天后大鼠制备肝微粒体的相应活性低75%、48%、29%和38%。蛋白质印迹分析表明，氯胺酮诱导的P-450 2B1/2蛋白在4天内也呈时间依赖性下降。在肝毒性研究中，用1ml/kg CCl4处理大鼠使血清丙氨酸转氨酶活性水平增加7倍，而在预先用80mg/kg氯胺酮处理4天的大鼠中增加17倍。用120mg/kg可卡因处理ICR小鼠导致17%的死亡率，而相同剂量的可卡因在预先用氯胺酮处理的小鼠中导致50%的死亡率。用100mg/kg可卡因处理小鼠使血清丙氨酸转氨酶活性水平增加76倍，而在预先用80mg/kg氯胺酮处理4天的小鼠中增加260倍。本研究表明，氯胺酮诱导大鼠肝微粒体中多种形式的P-450表达，并增加CCl4诱导的肝毒性和可卡因介导的急性毒性。与氯胺酮使用相关的其他潜在药理或毒理事件需要进一步探索。
