title: 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 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 (Cl(int); formation of OH-CZX per milligram protein) was comparable in both groups of rats. As a result, the relative Cl(int) 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 microg x min/ml, respectively; p.o., 1540 +/- 338 and 2170 +/- 1070 microg x min/ml, respectively). In LCD rats, the AUC(OH-CZX)/AUC(CZX) 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.
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
authors: Choong Y
authors: CY
authors: Ahn
authors: Soo K
authors: SK
authors: Bae
authors: Young S
authors: YS
authors: Jung
authors: Inchul
authors: I
authors: Lee
authors: Young C
authors: YC
authors: Kim
authors: Myung G
authors: MG
authors: Lee
authors: Wan G
authors: WG
authors: Shin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D002753:Chlorzoxazone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D007262:Infusions, Intravenous; D007668:Kidney / Q000503:physiopathology; D008099:Liver / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000150:complications* / Q000503:physiopathology; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000503:physiopathology
chemical_list: D001798:Blood Proteins; C039289:6-hydroxychlorzoxazone; D002753:Chlorzoxazone