Cytochrome P450 mediated-drug metabolism is reduced in children with sepsis-induced multiple organ failure

Intensive Care Med. 2003 Jun;29(6):980-984. doi: 10.1007/s00134-003-1758-3. Epub 2003 Apr 16.


Objective: Antipyrine metabolism is a "gold standard" measure of mixed cytochrome P450 (CYP) mediated drug metabolism in humans. Cytokines (e.g., interleukin-6) and nitric oxide reduce CYP 450 activity in vitro and in vivo. Because interleukin-6 and nitric oxide production increases in children with sepsis-induced multiple organ failure, we hypothesized impaired CYP 450 mediated drug metabolism in this population.

Methods: Fifty-one consecutive children with sepsis and six critically ill children without sepsis were enrolled and given 18 mg/kg antipyrine per NG. Plasma antipyrine elimination rate, elimination half-life, and apparent oral clearance were measured and calculated. Plasma interleukin-6 and nitrite plus nitrate levels were measured and organs failing scored on days 1-3 of sepsis.

Results: Children with sepsis had a twofold reduction in antipyrine clearance. Children with persistent failure of three or more organs had a fourfold reduction in antipyrine clearance. Antipyrine clearance was inversely correlated to circulating interleukin-6 and nitrite plus nitrate levels and to number of organ failures.

Conclusions: Interpretation CYP 450 mediated drug metabolism is decreased in children with sepsis, related in part to the degree of inflammation and organ failure. For drugs metabolized by CYP 450 enzymes there is an urgent need to reevaluate the use of standard drug dosage schedules in the sepsis population

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Age Factors
  • Analysis of Variance
  • Antipyrine / metabolism
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Critical Illness
  • Cytochrome P-450 Enzyme System / metabolism*
  • Humans
  • Infant
  • Infant, Newborn
  • Inflammation
  • Interleukin-6 / blood
  • Interleukin-6 / immunology
  • Metabolic Clearance Rate
  • Multiple Organ Failure / immunology
  • Multiple Organ Failure / metabolism*
  • Multiple Organ Failure / microbiology*
  • Multiple Organ Failure / mortality
  • Nitrates / blood
  • Nitric Oxide / immunology
  • Nitrites / blood
  • Pharmaceutical Preparations / metabolism*
  • Regression Analysis
  • Sepsis / complications*
  • Severity of Illness Index
  • Survival Analysis


  • Interleukin-6
  • Nitrates
  • Nitrites
  • Pharmaceutical Preparations
  • Nitric Oxide
  • Cytochrome P-450 Enzyme System
  • Antipyrine