Nosaka Hiroyuki, Nadai Masayuki, Kato Miki, Yasui Kazumasa, Yoshizumi Hideo, Miyoshi Mika, Zhao Ying Lan, Baba Kenji, Takagi Kenzo, Hasegawa Takaaki
Department of Medical Technology, Nagoya University School of Health Sciences, Daikominami, Higashi-ku, Nagoya 461-8673, Japan.
Life Sci. 2006 May 30;79(1):50-6. doi: 10.1016/j.lfs.2005.12.022. Epub 2006 Jan 19.
The effects of a newly-developed ketolide antibiotic, telithromycin, on the metabolism of theophylline and the expression of hepatic cytochrome P450 (CYP) 1A2 and CYP3A2 were investigated in rats. Telithromycin at a high dose (100 mg/kg of body weight) was injected intraperitoneally once a day for 3 days. Twenty-four hours (day 4) after the final administration of telithromycin, theophylline (10 mg/kg) was administered intravenously. The presence of telithromycin significantly delayed the disappearance of theophylline from plasma. Parameters related to the pharmacokinetic interaction between theophylline and telithromycin were examined by noncompartmental methods. A significant decrease in the systemic clearance of theophylline was observed in the presence of telithromycin. Pretreatment with telithromycin significantly decreased the metabolic clearance of the major metabolites, 1-methyluric acid and 1,3-dimethyluric acid, with no change in the renal clearance of theophylline, suggesting that the decreased systemic clearance of theophylline by telithromycin is due to reduction of their metabolic clearance. Pretreatment with telithromycin significantly decreased the activity of 7-ethoxyresorufin O-deethylation and testosterone 6 beta-hydroxylation, suggesting that telithromycin decreases the activity of hepatic CYP1A2 and CYP3A2. Western blot analysis revealed that telithromycin significantly decreased the protein levels of CYP1A2 and CYP3A2 in the liver, which could explain the observed decreases in the systemic clearance of theophylline and metabolic clearance of 1-methyluric acid and 1,3-dimethyluric acid. The present study suggests that telithromycin at the dose used in this study alters the pharmacokinetics and metabolism of theophylline, due to reductions in the activity and expression of hepatic CYP1A2 and CYP3A2.
在大鼠中研究了一种新开发的酮内酯类抗生素泰利霉素对茶碱代谢以及肝细胞色素P450（CYP）1A2和CYP3A2表达的影响。以高剂量（100mg/kg体重）的泰利霉素腹腔注射，每天1次，共3天。在最后一次给予泰利霉素后24小时（第4天），静脉注射茶碱（10mg/kg）。泰利霉素的存在显著延迟了茶碱从血浆中的消失。采用非房室模型方法检测了茶碱与泰利霉素之间药代动力学相互作用的相关参数。在存在泰利霉素的情况下，观察到茶碱的全身清除率显著降低。泰利霉素预处理显著降低了主要代谢产物1-甲基尿酸和1,3-二甲基尿酸的代谢清除率，而茶碱的肾清除率无变化，这表明泰利霉素使茶碱全身清除率降低是由于其代谢清除率降低所致。泰利霉素预处理显著降低了7-乙氧基异吩恶唑酮O-脱乙基酶活性和睾酮6β-羟化酶活性，提示泰利霉素降低了肝脏CYP1A2和CYP3A2的活性。蛋白质印迹分析显示，泰利霉素显著降低了肝脏中CYP1A2和CYP3A2的蛋白水平，这可以解释观察到的茶碱全身清除率以及1-甲基尿酸和1,3-二甲基尿酸代谢清除率的降低。本研究提示，本研究中使用的剂量的泰利霉素改变了茶碱的药代动力学和代谢，原因是肝脏CYP1A2和CYP3A2的活性和表达降低。
