Dhondt Laura, Croubels Siska, De Paepe Peter, Goethals Klara, De Cock Pieter, Devreese Mathias
Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Front Pharmacol. 2021 Jan 26;11:607101. doi: 10.3389/fphar.2020.607101. eCollection 2020.
Augmented renal clearance (ARC) observed in the critically ill pediatric population has received an increased attention over the last years due to its major impact on the disposition and pharmacokinetics of mainly renally excreted drugs. Apart from an important inflammatory trigger, fluid administration has been suggested to contribute to the development of ARC. Therefore, the primary objective of this study was to evaluate the effect of continuous intravenous fluid administration on renal function using a conventional piglet animal model and to quantify the impact of fluid administration on the pharmacokinetics of renally excreted drugs. At baseline, twenty-four piglets (12 treatment/12 control; 7 weeks old, all ♂) received the marker drugs iohexol (64.7 mg/kg body weight (BW)) and para-aminohippuric acid (10 mg/kg BW) to quantify glomerular filtration rate and effective renal plasma flow, respectively. In addition, the hydrophilic antibiotic amikacin (7.5 mg/kg BW) was administered. Following this baseline measurement, the treatment group received fluid therapy as a constant rate infusion of 0.9% saline at 6 mL/kg/h over 36 h. After 24 h of fluid administration, the marker drugs and amikacin were administered again. When comparing both groups, a significant effect of fluid administration on the total body clearances of iohexol ( = 0.032) and amikacin ( = 0.0014) was observed. Clearances of iohexol and amikacin increased with on average 15 and 14%, although large interindividual variability was observed. This led to decreased systemic exposure to amikacin, which was manifested as decrease in area under the plasma concentration-time curve from time 0 h to infinity from 34,807 to 30,804 ng.h/mL. These results suggest that fluid therapy is a key factor involved in the development of ARC and should be taken into account when administering mainly renally excreted drugs. However, further research is necessary to confirm these results in children.
近年来，危重症儿科患者中观察到的肾脏清除率增加（ARC）受到了更多关注，因为它对主要经肾脏排泄药物的处置和药代动力学有重大影响。除了重要的炎症触发因素外，液体输注也被认为与ARC的发生有关。因此，本研究的主要目的是使用传统的仔猪动物模型评估持续静脉输注液体对肾功能的影响，并量化液体输注对经肾脏排泄药物药代动力学的影响。在基线时，24只仔猪（12只治疗组/12只对照组；7周龄，均为雄性）接受了标记药物碘海醇（64.7mg/kg体重（BW））和对氨基马尿酸（10mg/kg BW），分别用于量化肾小球滤过率和有效肾血浆流量。此外，还给予了亲水性抗生素阿米卡星（7.5mg/kg BW）。在进行基线测量后，治疗组接受了36小时的液体治疗，以6mL/kg/h的恒定速率输注0.9%生理盐水。在液体输注24小时后，再次给予标记药物和阿米卡星。比较两组时，观察到液体输注对碘海醇（P = 0.032）和阿米卡星（P = 0.0014）的全身清除率有显著影响。碘海醇和阿米卡星的清除率平均分别增加了15%和14%，尽管观察到个体间存在较大差异。这导致阿米卡星的全身暴露减少，表现为血浆浓度-时间曲线下面积从0小时到无穷大时从34,807降至30,804ng·h/mL。这些结果表明，液体治疗是ARC发生的关键因素，在给予主要经肾脏排泄的药物时应予以考虑。然而，需要进一步的研究来在儿童中证实这些结果。
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