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The effect of endotoxin administration on the pharmacokinetics of chlorzoxazone in humans
Author(s) -
Poloyac Samuel M.,
Tosheva Raina T.,
Gardner Brian M.,
Shedlofsky Steven I.,
Blouin Robert A.
Publication year - 1999
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1053/cp.1999.v66.103172001
Subject(s) - chlorzoxazone , lipopolysaccharide , pharmacology , lipopolysaccharide binding protein , pharmacokinetics , chemistry , cytokine , medicine , acute phase protein , inflammation , cyp2e1 , metabolism , cytochrome p450
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. Clinical Pharmacology & Therapeutics (1999) 66 , 554–562; doi: 10.1053/cp.1999.v66.103172001