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 (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.
Footnotes
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This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Korea (A050376).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.017442.
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ABBREVIATIONS: CZX, chlorzoxazone; OH-CZX, 6-hydroxychlorzoxazone; P450, cytochrome P450; AUC, total area under the plasma concentration–time curve from time zero to time infinity; HPLC, high-performance liquid chromatography; LC, liver cirrhosis; DM, diabetes mellitus; LCD, liver cirrhosis with diabetes mellitus; GOT, glutamate oxaloacetate transaminase; GPT, glutamate pyruvate transaminase; LDH, lactate dehydrogenase; PBS-T, phosphate-buffered saline/Tween 20; Clint, intrinsic clearance; Cl, time-averaged total body clearance; Clr, time-averaged renal clearance; Clnr, time-averaged non-renal clearance; Clcr, creatinine clearance; MRT, mean residence time; Vss, apparent volume of distribution at steady state; F, extent of absolute oral bioavailability; Ae0–24 h, percentage of the dose excreted in the 24-h urine; GI24 h, percentage of the dose recovered from the entire gastrointestinal tract (including its contents and feces) at 24 h.
- Received June 26, 2007.
- Accepted March 27, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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