TY - JOUR T1 - Pharmacokinetic Parameters of Chlorzoxazone and Its Main Metabolite, 6-Hydroxychlorzoxazone, after Intravenous and Oral Administration of Chlorzoxazone to Liver Cirrhotic Rats with Diabetes Mellitus JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1233 LP - 1241 DO - 10.1124/dmd.107.017442 VL - 36 IS - 7 AU - Choong Y. Ahn AU - Soo K. Bae AU - Young S. Jung AU - Inchul Lee AU - Young C. Kim AU - Myung G. Lee AU - Wan G. Shin Y1 - 2008/07/01 UR - http://dmd.aspetjournals.org/content/36/7/1233.abstract N2 - 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 been 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 [liver cirrhosis with diabetes mellitus (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 (Clint; formation of OH-CZX per milligram protein) was comparable in both groups of rats. As a result, the relative Clint was also comparable for the two groups. Thus, OH-CZX formation in LCD and control rats was expected to be similar. As expected, after i.v. (20 mg/kg) and p.o. (50 mg/kg) administration of CZX, the area under the curve (AUC) of OH-CZX was comparable in control and LCD rats (i.v., 571 ± 85.8 and 578 ± 413 μg · min/ml, respectively; p.o., 1540 ± 338 and 2170 ± 1070 μg · min/ml, respectively). In LCD rats, the AUCOH-CZX/AUCCZX ratio was similar to the value in control rats after i.v. and p.o. administration. These results indicate that OH-CZX can be used as a chemical probe to assess the activity of CYP2E1 in LCD rats. The American Society for Pharmacology and Experimental Therapeutics ER -