Carcillo Joseph A, Doughty Lesley, Kofos Danny, Frye Reginald F, Kaplan Sandra S, Sasser Howell, Burckart Gilbert J
Division of Critical Care Medicine, Children's Hospital of Pittsburgh, 3705 5th Ave, Pittsburgh, PA, 15123, USA.
Department of Anesthesiology and Critical Care Medicine and Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Intensive Care Med. 2003 Jun;29(6):980-984. doi: 10.1007/s00134-003-1758-3. Epub 2003 Apr 16.
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.
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.
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.
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
安替比林代谢是衡量人体中细胞色素P450（CYP）介导的混合药物代谢的“金标准”。细胞因子（如白细胞介素-6）和一氧化氮在体外和体内均可降低CYP 450活性。由于脓毒症诱导的多器官功能衰竭患儿体内白细胞介素-6和一氧化氮的产生增加，我们推测该人群中CYP 450介导的药物代谢受损。
纳入51例连续的脓毒症患儿和6例无脓毒症的危重症患儿，经鼻饲给予18mg/kg安替比林。测定并计算血浆安替比林消除率、消除半衰期和表观口服清除率。在脓毒症第1 - 3天测量血浆白细胞介素-6和亚硝酸盐加硝酸盐水平，并对衰竭器官进行评分。
脓毒症患儿的安替比林清除率降低了两倍。三个或更多器官持续衰竭的患儿安替比林清除率降低了四倍。安替比林清除率与循环白细胞介素-6、亚硝酸盐加硝酸盐水平以及器官衰竭数量呈负相关。
脓毒症患儿中CYP 450介导的药物代谢降低，部分与炎症程度和器官衰竭有关。对于由CYP 450酶代谢的药物，迫切需要重新评估脓毒症人群中标准药物剂量方案的使用情况。
