Cytochrome P450 mediated-drug metabolism is reduced in children with sepsis-induced multiple organ failure.
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
Carcillo
Joseph A
JA
Division of Critical Care Medicine, Children's Hospital of Pittsburgh, 3705 5th Ave, Pittsburgh, PA, 15123, USA. carcilloja@ccm.upmc.edu.|Department of Anesthesiology and Critical Care Medicine and Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA. carcilloja@ccm.upmc.edu.|Center for Clinical Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA. carcilloja@ccm.upmc.edu.
Doughty
Lesley
L
Department of Anesthesiology and Critical Care Medicine and Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Kofos
Danny
D
Department of Anesthesiology and Critical Care Medicine and Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Frye
Reginald F
RF
Center for Clinical Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.|School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Kaplan
Sandra S
SS
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
Sasser
Howell
H
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Burckart
Gilbert J
GJ
Center for Clinical Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.|School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
D000293:Adolescent; D000367:Age Factors; D000704:Analysis of Variance; D000983:Antipyrine / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D008657:Metabolic Clearance Rate; D009102:Multiple Organ Failure / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology* / Q000401:mortality; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000276:immunology; D009573:Nitrites / Q000097:blood; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012044:Regression Analysis; D018805:Sepsis / Q000150:complications*; D012720:Severity of Illness Index; D016019:Survival Analysis
D015850:Interleukin-6; D009566:Nitrates; D009573:Nitrites; D004364:Pharmaceutical Preparations; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D000983:Antipyrine