Effect of the acute-phase response on the pharmacokinetics of chlorzoxazone and cytochrome P-450 2E1 in vitro activity in rats

Abstract

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.