title: Obesity-induced increase of CYP2E1 activity and its effect on disposition kinetics of chlorzoxazone in Zucker rats.
abstract: This study was designed to investigate the induction of CYP2E1 in obese Zucker rats and its effect on the disposition kinetics of chlorzoxazone (CZX). CZX 20mg/kg was administered to three groups of rats: normal Zucker rats fed a normal diet (ND), normal Zucker rats fed a high-fat diet (HF), and genetically obese Zucker rats fed a normal diet (OB). The values of the area under the plasma concentration-time curve from 0 to infinity (AUC(infinity)) of CZX were in the order of ND>HF>OB rats. The AUC(infinity) values of total 6-hydroxychlorzoxazone (6OHCZX-T), which is considered to be a CYP2E1 metabolic marker, were in the opposite order. The values of the AUC(infinity) ratio (6OHCZX-T/CZX) in ND, HF and OB rats were approximately 0.2, 0.3 and 0.4, respectively. The CZX concentration in fat was much higher than the concentrations in plasma, liver and kidney in all groups. Induction of CYP2E1 protein was greater in both liver and fat of OB rats than in those of HF rats. Microsomal activity of CYP2E1 in liver and fat was also in the order of OB>HF>NM rats. These results suggest that CYP2E1 may be induced in liver and fat of obese patients, thereby potentially altering the disposition kinetics of not only CZX, but also other lipophilic drugs metabolized by CYP2E1.
authors.affiliation: Department of Medicinal Informatics, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Japan.
authors.forename: Phisit
authors.initials: P
authors.lastname: Khemawoot
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokogawa
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimada
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001483:Base Sequence; D002753:Chlorzoxazone / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D008297:Male; D009125:Muscle Relaxants, Central / Q000493:pharmacokinetics*; D009765:Obesity / Q000201:enzymology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker
chemical_list: D017931:DNA Primers; D009125:Muscle Relaxants, Central; D012333:RNA, Messenger; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone