Obesity-induced increase of CYP2E1 activity and its effect on disposition kinetics of chlorzoxazone in Zucker rats
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This study was designed to investigate the induction of CYP2E1 in obese Zucker rats and itseffect on the disposition kinetics of chlorzoxazone (CZX). CZX 20 mg/kg was administered tothree groups of rats: normal Zucker rats fed a normal diet (ND), normal Zucker rats fed ahigh-fat diet (HF), and genetically obese Zucker rats fed a normal diet (OB). The values of thearea under the plasma concentration–time curve from 0 to 1 (AUC1) of CZX were in theorder of ND > HF > OB rats. The AUC1 values of total 6-hydroxychlorzoxazone (6OHCZX-T),which is considered to be a CYP2E1 metabolic marker, were in the opposite order. The valuesof the AUC1 ratio (6OHCZX–T/CZX) in ND, HF and OB rats were approximately 0.2, 0.3 and0.4, respectively. The CZX concentration in fat was much higher than the concentrations inplasma, liver and kidney in all groups. Induction of CYP2E1 protein was greater in both liverand fat of OB rats than in those of HF rats. Microsomal activity of CYP2E1 in liver and fat wasalso in the order of OB > HF > NMrats. These results suggest that CYP2E1 may be induced inliver and fat of obese patients, thereby potentially altering the disposition kinetics of notonly CZX, but also other lipophilic drugs metabolized by CYP2E1.©2006 Published by Elsevier Inc.
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