title: Pharmacokinetics of a cytochrome P450 2E1 probe, chlorzoxazone, and its 6-hydroxy metabolite in poloxamer 407-induced hyperlipidemic rats.
abstract: OBJECTIVE
  To evaluate the possible changes in CYP2E1 expression and activity in hyperlipidemia (HL), we evaluated the pharmacokinetics of chlorzoxazone (CZX) as a CYP2E1 probe in rats with HL induced by poloxamer 407 (HL rats).
  
  
  METHODS
  The pharmacokinetics of CZX and its 6-hydroxy metabolite (OH-CZX) were evaluated after intravenous administration of 20 mg/kg CZX to both control and HL rats. We also examined changes in the expression of CYP2E1 and its in vitro metabolic activity in hepatic microsomal fractions from HL rats.
  
  
  RESULTS
  The total area under the plasma concentration-time curve (AUC) of CZX in the HL rats after its intravenous administration was comparable with that in the controls due to unchanged non-renal clearance (CLNR). The AUC of OH-CZX and AUCOH-CZX/AUCCZX ratios in HL rats also remained unchanged. This was primarily due to the comparable hepatic CLint for metabolism of CZX to OH-CZX via CYP2E1 between the control and HL rats as a result of unchanged expression of CYP2E1 in HL rats.
  
  
  CONCLUSIONS
  This is the first study to evaluate CYP2E1 expression and activity in HL rats and their effects on the pharmacokinetics of a CYP2E1 probe drug. These findings have potential therapeutic implications assuming that the HL rat model qualitatively reflects similar changes in patients with HL.
authors.affiliation: College of Pharmacy, The Catholic University of Korea.
authors.forename: Mi Hye
authors.initials: MH
authors.lastname: Kwon
authors.forename: Cheol Jung
authors.initials: CJ
authors.lastname: Lee
authors.forename: Yong Yeon
authors.initials: YY
authors.lastname: Cho
authors.forename: Hee Eun
authors.initials: HE
authors.lastname: Kang
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002753:Chlorzoxazone / Q000097:blood / Q000493:pharmacokinetics*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D006949:Hyperlipidemias / Q000139:chemically induced / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D020442:Poloxamer; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001798:Blood Proteins; D020442:Poloxamer; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone