Rockich K, Blouin R
Division of Pharmaceutical Sciences, University of Kentucky, College of Pharmacy, Lexington, Kentucky 40536-0082, USA.
Drug Metab Dispos. 1999 Sep;27(9):1074-7.
The acute-phase response is known to produce alterations in hepatic cytochrome P-450 (CYP) expression. Lipopolysaccharide (LPS), a well known inducer of acute-phase response decreases hepatic CYP2E1 in vitro activity in rats. This study was designed to determine if LPS administration produced alterations in the pharmacokinetics of chlorzoxazone (CZN), a marker for CYP2E1 expression. Sprague-Dawley rats were administered a single i.p. injection of LPS (5 mg/kg) or saline control approximately 24 h before a single i.v. bolus dose of CZN (15 mg/kg). Serial blood samples were collected over a 120-min period to quantitate CZN plasma concentrations and protein binding. In addition, livers were removed and processed for evaluating in vitro CYP2E1 protein concentrations and activity. Systemic clearance decreased by 35% in LPS-treated rats, whereas half-life and steady-state volume of distribution increased by 167 and 66%, respectively. The plasma free-fraction of CZN increased 2-fold after LPS treatment. The CZN intrinsic clearance decreased in LPS rats by 71% compared with control values. The CYP2E1 liver microsomal activity decreased between 55 and 75% along with a 41% decrease in CYP2E1 protein concentration. The CZN intrinsic clearance was significantly correlated with both the CZN and p-nitrophenol liver microsomal activity (r = 0.97 and r = 0.91, respectively). This study demonstrated that LPS administration produced expected reductions in the in vivo intrinsic clearance of CZN, and these changes were highly correlated with in vitro activity studies. In addition, LPS produced significant increases in the steady-state volume of distribution of CZN secondary to reductions in its plasma protein binding.
已知急性期反应会引起肝细胞色素P-450（CYP）表达的改变。脂多糖（LPS）是一种著名的急性期反应诱导剂，它会降低大鼠体外CYP2E1的活性。本研究旨在确定给予LPS是否会改变氯唑沙宗（CZN）的药代动力学，CZN是CYP2E1表达的标志物。在单次静脉推注CZN（15mg/kg）前约24小时，给Sprague-Dawley大鼠单次腹腔注射LPS（5mg/kg）或生理盐水对照。在120分钟内采集系列血样以定量CZN血浆浓度和蛋白结合率。此外，取出肝脏并进行处理以评估体外CYP2E1蛋白浓度和活性。LPS处理的大鼠全身清除率降低了35%，而半衰期和稳态分布容积分别增加了167%和66%。LPS处理后，CZN的血浆游离分数增加了2倍。与对照值相比，LPS大鼠中CZN的内在清除率降低了71%。CYP2E1肝微粒体活性降低了55%至75%，同时CYP2E1蛋白浓度降低了41%。CZN的内在清除率与CZN和对硝基苯酚肝微粒体活性均显著相关（r分别为0.97和0.91）。本研究表明，给予LPS会使CZN的体内内在清除率出现预期的降低，并且这些变化与体外活性研究高度相关。此外，由于CZN血浆蛋白结合率降低，LPS使CZN的稳态分布容积显著增加。
