Pharmacokinetic Parameters of Chlorzoxazone and its Main Metabolite, 6-Hydroxychlorzoxazone, after Intravenous and Oral Administration of Chlorzoxazone to Liver Cirrhotic Rats with Diabetes Mellitus. Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] Journal article | | 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. | | Author(s) | Ahn CY, Bae SK, Jung YS, Lee I, Kim YC, Lee MG, Shin WG | | Institution | Korean Food & Drug Administration. | | Source | Drug Metab Dispos 2008 Mar 31. | | 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 (Clint; formation of OH-CZX per mg protein) was comparable in both groups of rats. As a result, the relative Clint was also comparable for the two groups; Clint 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 microg.min/ml, respectively; oral, 1540 +/-338 and 2170 +/-1070 microg.min/ml, respectively). In LCD rats, the AUCOH-CZX / AUCCZX 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 18378564 |
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