Received for publication June 27, 2007.
Revised March 27, 2008.
Accepted for publication March 27, 2008.

Pharmacokinetic Parameters of Chlorzoxazone and its Main Metabolite, 6-Hydroxychlorzoxazone, after Intravenous and Oral Administration of Chlorzoxazone to Liver Cirrhotic Rats with Diabetes Mellitus

Abstract

Protein expression of the hepatic CYP2E1 has been reported to be increased in diabetic rats. This enzyme is the primary metabolizer of chlorzoxazone (CZX) to 6-hydroxychlorzoxazone (OH-CZX). Although patients with liver cirrhosis have a higher prevalence of diabetes mellitus, there have no reported studies on the protein expression of CYP2E1 in rats induced to have liver cirrhosis and diabetes mellitus by injection of N-dimethylnitrosamine followed by streptozotocin (LCD rats). Thus, in the present study, the pharmacokinetics of CZX and OH-CZX were evaluated in LCD rats. Compared with control rats, LCD rats had significantly decreased (by 62%) total liver protein and significantly increased (by 124%) protein expression of CYP2E1, but the intrinsic clearance (Cl_int; formation of OH-CZX per mg protein) was comparable in both groups of rats. As a result, the relative Cl_int was also comparable for the two groups; Cl_int for the LCD rats was 13% greater than that of the control rats. Thus, OH-CZX formation in LCD and control rats was expected to be similar. As expected, after intravenous (20 mg/kg) and oral (50 mg/kg) administration of CZX, the total area under the plasma OH-CZX concentration-time curve (AUC) was comparable in control and LCD rats (intravenous, 571± 85.8 and 578 ±413 µg·min/ml, respectively; oral, 1540 ±338 and 2170 ±1070 µg·min/ml, respectively). In LCD rats, the AUC_OH-CZX / AUC_CZX ratio was simialar to value in control rats after intravenous and oral administration. These results indicate that OH-CZX can be used as a chemical probe to assess the activity of CYP2E1 in LCD rats.

Key words: CYP induction, CYP2E, HPLC, in vivo probes, liver disease, metabolite kinetics, pharmacokinetics