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

Carcillo, Joseph A.; Doughty, Lesley; Kofos, Danny; Frye, Reginald F.; Kaplan, Sandra S.; Sasser, Howell; Burckart, Gilbert J.

doi:10.1007/s00134-003-1758-3

Cited by 133 publications

(78 citation statements)

References 20 publications

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“…There are two possibilities that explain the decrease in P450 expression after RBC transfusion: (1) degradation of P450 enzymes by ischemia-reperfusion and (2) inhibition of the biosynthesis of P450 enzymes by ischemia-reperfusion. There is now a substantial body of evidence to support the notion that many of the pathophysiological events triggered by ischemia-reperfusion injury are mediated through the production of reactive oxygen species (ROS) and to the subsequent secretion of inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) (Carcillo et al, 2003). Previous studies clearly showed that these cytokines and ROS cause a decrease in P450 expression resulting from an enhancement in P450 degradation (Thelen and Dressman, 2009;Vee et al, 2009;Weaver, 2009).…”

Section: Discussionmentioning

confidence: 99%

Carbon Monoxide–Bound Red Blood Cells Protect Red Blood Cell Transfusion-Induced Hepatic Cytochrome P450 Impairment in Hemorrhagic-Shock Rats

et al. 2012

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Red blood cell (RBC) transfusions for massive hemorrhage induce systemic ischemic-reperfusion and influence the disposition and pharmacological activity of drugs as a result of a reduction in the level of expression and activity of cytochrome P450s (P450). It was reported that, when organ-preserving solutions are exposed to carbon monoxide (CO), the treatment was effective in suppressing the postreperfusion reduction in renal P450 levels in cases of kidney transplantation. Therefore, we hypothesized that transfusions with RBC that contain bound CO (CO-RBC) would protect the hepatic level of rat P450 during a massive hemorrhage, compared with plasma expanders and RBC resuscitation. To achieve this, we created 40% hemorrhagic-shock model rats, followed by resuscitation, with use of recombinant human serum albumin, RBCs, and CO-RBCs. At 1 hour after resuscitation, the expressions of hepatic P450 isoforms (1A2, 2C11, 2E1, and 3A2) were significantly decreased in the RBC resuscitation group, compared with the sham group. Such alterations in hepatic P450 significantly resulted in an increase in the plasma concentrations of substrate drugs (caffeine [1A2], tolbutamide [2C11], chlorzoxazone [2E1], and midazolam [3A2]) for each P450 isoform, and thus, the hypnotic action of midazolam could be significantly prolonged. Of interest, the reductions in hepatic P450 activity observed in the RBC group were significantly suppressed by CO-RBC resuscitation, and consequently, the pharmacokinetics of substrate drugs and the pharmacological action of midazolam remained at levels similar to those under sham conditions. These results indicate that CO-RBC resuscitation has considerable potential in terms of achieving safe and useful drug therapy during massive hemorrhages.

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Section: Discussionmentioning

confidence: 99%

Carbon Monoxide–Bound Red Blood Cells Protect Red Blood Cell Transfusion-Induced Hepatic Cytochrome P450 Impairment in Hemorrhagic-Shock Rats

et al. 2012

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“…16 Moreover, the impact of pathophysiological changes on pharmacokinetics has been widely demonstrated in critically ill adults. [17][18][19] The aims of this study were therefore (i) to investigate the pharmacokinetics of intravenous piperacillin and tazobactam in critically ill infants and children, and (ii) to revisit the dose rationale of the drug combination and evaluate the efficacy of current and alternative dosing regimens in this population based on PK/PD indices.…”

Section: Introductionmentioning

confidence: 99%

Dose optimization of piperacillin/tazobactam in critically ill children

Cock¹,

Dijkman

Jaeger

et al. 2017

Journal of Antimicrobial Chemotherapy

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Running title: Paediatric piperacillin/tazobactam dose rationale SynopsisObjectives. The aim of this study was to characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen.Patients and Methods. This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg q6h based on piperacillin). Piperacillin/tazobactam concentrations were measured by a liquid chromatography-tandem mass spectrometry method. Pharmacokinetic data was analysed using nonlinear mixed effects modelling.Results. Piperacillin and tazobactam blood samples were collected from 47 patients (median age: 2.83 years; range: 2 months -15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model which included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 L/h and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) q4h over 2 hours, 100 mg/kg q4h given over 1 hour or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24h were minimally required to achieve the therapeutic targets for piperacillin (60 % fT>MIC>16 mg/L). Conclusion. Standard intermittent dosing regimens do not ensure optimalpiperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age.

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“…Infectious and inflammatory diseases in humans, or diseases with an inflammatory component, are associated with decreased clearances of several CYP substrates [2][3][4][5], and increased incidence of adverse effects of drugs with a low therapeutic index like theophylline [2] CYPselective effects have been inferred from the clearance of diagnostic substrates [6]. Moreover, many of these effects can be recapitulated in human hepatocyte cultures exposed to inflammatory cytokines [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Roles of nitric oxide in inflammatory downregulation of human cytochromes P450

Aitken

Lee

Morgan

2008

Free Radical Biology and Medicine

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The purpose of this study was to determine the role of nitric oxide (NO) in the down-regulation of human CYP enzymes and mRNAs by an inflammatory stimulus in cultured human hepatocytes. We focused on CYP2B6, because previous studies showed that rat CYP2B proteins undergo an NOdependent degradation in response to inflammatory stimuli. To ensure high level expression of CYP2B6, the inducer phenytoin was present at all times. Stimulation of cells with a mixture of TNFα, IL-1β and IFNγ (ILmix) down-regulated CYP2B6 mRNA and protein to 9% and 19% of control levels. The NO donor NOC-18 down-regulated CYP2B6 protein to 30% of control, with only a small effect on CYP2B6 mRNA. NOS inhibitors attenuated the down-regulation of CYP2B6 protein, but not mRNA, by ILmix. These findings demonstrate that the post-transcriptional NO dependent down-regulation of CYP2B enzymes, observed previously in rat hepatocytes, is conserved in human CYP2B6. This mechanism is specific for CYP2B6 among the enzymes tested. No evidence was found for regulation of CYP2E1 mRNA or protein by NO. NOC-18 treatment down-regulated CYP3A4 mRNA to 50% of control. However, NOS inhibitors failed to block the effects of ILmix on CYP3A4 expression.

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

Cited by 133 publications

References 20 publications

Carbon Monoxide–Bound Red Blood Cells Protect Red Blood Cell Transfusion-Induced Hepatic Cytochrome P450 Impairment in Hemorrhagic-Shock Rats

Carbon Monoxide–Bound Red Blood Cells Protect Red Blood Cell Transfusion-Induced Hepatic Cytochrome P450 Impairment in Hemorrhagic-Shock Rats

Dose optimization of piperacillin/tazobactam in critically ill children

Roles of nitric oxide in inflammatory downregulation of human cytochromes P450

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