title: The effect of endotoxin administration on the pharmacokinetics of chlorzoxazone in humans.
abstract: OBJECTIVE
  Inflammation induced by Escherichia coli lipopolysaccharide alters the clearance of several hepatically eliminated drugs. Extensive rat liver research has shown CYP2E1 down-regulation after lipopolysaccharide administration. To further investigate this phenomenon in humans, lipopolysaccharide was administered to healthy male volunteers and chlorzoxazone was used as a CYP2E1 probe drug.
  
  
  METHODS
  Twelve healthy men were given 500 mg oral chlorzoxazone after two daily lipopolysaccharide doses (20 endotoxin units/kg/day) and again after administration of saline solution in this balanced crossover study. Serum and urine chlorzoxazone and 6-hydroxychlorzoxazone were quantified, as well as cytokine and C-reactive protein levels.
  
  
  RESULTS
  Lipopolysaccharide produced the expected induction of the acute-phase response shown by elevations in tumor necrosis factor, interleukin-6, C-reactive protein, and temperature. Lipopolysaccharide treatment failed to produce a significant change in the chlorzoxazone oral clearance (4.4 +/- 0.9 mL/min/kg for lipopolysaccharide versus 4.2 +/- 1.4 mL/min/kg for control) or the 6-hydroxychlorzoxazone formation clearance (2.8 +/- 0.65 mL/min/kg for lipopolysaccharide versus 2.5 +/- 0.9 mL/min/kg for control). The high intersubject variabilities in oral clearance and formation clearance were not accounted for by changes in protein binding, cytokine, or C-reactive protein values. In contrast, a significant increase in the 6-hydroxychlorzoxazone glucuronide renal clearance was observed (7.5 +/- 1.37 mL/min/kg for lipopolysaccharide versus 6.1 +/- 1.7 mL/min/kg for control).
  
  
  CONCLUSIONS
  This study showed that the inflammatory response to lipopolysaccharide (20 endotoxin units/kg/day for 2 days) in humans does not consistently alter chlorzoxazone hepatic metabolism. However, the significant increase in renal clearance of the glucuronidated metabolite suggests that renal tubular secretion may be increased in humans with acute endotoxemia.
authors.affiliation: University of Kentucky College of Pharmacy and Department of Medicine, Veterans Affairs Hospital, Lexington, 40536-0082, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Poloyac
authors.forename: R T
authors.initials: RT
authors.lastname: Tosheva
authors.forename: B M
authors.initials: BM
authors.lastname: Gardner
authors.forename: S I
authors.initials: SI
authors.lastname: Shedlofsky
authors.forename: R A
authors.initials: RA
authors.lastname: Blouin
mesh_terms: D000328:Adult; D002097:C-Reactive Protein / Q000378:metabolism; D002753:Chlorzoxazone / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D007684:Kidney Tubules / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects*; D008099:Liver / Q000378:metabolism; D008297:Male; D009125:Muscle Relaxants, Central / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D012016:Reference Values; D012709:Serum Albumin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D009125:Muscle Relaxants, Central; D012709:Serum Albumin; D014409:Tumor Necrosis Factor-alpha; C039289:6-hydroxychlorzoxazone; D002097:C-Reactive Protein; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone