医源性羟乙基淀粉诱导的低白蛋白血症期间头孢曲松的药代动力学：一种探索蛋白质结合能力降低对高结合药物影响的模型。

Ceftriaxone pharmacokinetics during iatrogenic hydroxyethyl starch-induced hypoalbuminemia: a model to explore the effects of decreased protein binding capacity on highly bound drugs.

作者信息

Mimoz O, Soreda S, Padoin C, Tod M, Petitjean O, Benhamou D

机构信息

Department of Anesthesia and Intensive Care, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France.

出版信息

Anesthesiology. 2000 Sep;93(3):735-43. doi: 10.1097/00000542-200009000-00023.

DOI:10.1097/00000542-200009000-00023

PMID:10969307

Abstract

BACKGROUND

Although various drugs used by anesthesiologists highly bind to plasma proteins, the impact of iatrogenically induced hypoproteinemia on their pharmacologic effects has never been investigated. The authors determined the pharmacokinetics of ceftriaxone, a cephalosporin that binds strongly to albumin in postsurgical patients with hydroxyethyl starch-induced hypoalbuminemia.

METHODS

Eleven hypoalbuminemic (serum albumin < 25 g/l) patients and age (+/- 5 yr)-, sex-, and body surface area (+/- 10%)-matched healthy volunteers received a 2-g ceftriaxone dose infused over a 15-min period. Fourteen venous blood samples were collected during the 24-h study period. Free ceftriaxone concentrations were determined by ultrafiltration. Antibiotic concentrations in plasma and ultrafiltrate were measured by ion-paired reversed-phase chromatography. The pharmacokinetic parameters derived from total and free antibiotic concentrations were determined using a noncompartmental method. Data are expressed as median and range.

RESULTS

The pharmacokinetic parameters derived from total ceftriaxone concentrations were similar for the two groups, except for the median corrected volume of distribution at steady state, which was increased (P = 0.05) to 0.18 l/kg (range, 0. 11-0.29 l/kg) in patients, compared with 0.15 l/kg (range, 0.13-0.22 l/kg) in volunteers. The area under the free ceftriaxone concentration-time curve was twice as high in patients as in volunteers (median 192, range 114-301 vs. median 122, range 84-169 h. mg-1. l-1;P = 0.03). Moreover, the free ceftriaxone concentration remained more than 4 mg/l during more time in patients (median, 16. 7; range, 12.6-21.4 vs. median, 11.1; range, 6.0-19.0 h; P = 0.03).

CONCLUSIONS

Compared with healthy volunteers, patients with iatrogenic hypoalbuminemia have higher free ceftriaxone concentrations during the 24 h after antibiotic administration. This modification increases drug distribution into extravascular space and may enhance effectiveness.

摘要

背景

尽管麻醉医生使用的各种药物与血浆蛋白高度结合，但医源性低蛋白血症对其药理作用的影响从未被研究过。作者测定了头孢曲松在因羟乙基淀粉导致低白蛋白血症的术后患者中的药代动力学，头孢曲松是一种与白蛋白强烈结合的头孢菌素。

方法

11名低白蛋白血症患者（血清白蛋白<25g/l）以及年龄（±5岁）、性别和体表面积（±10%）匹配的健康志愿者接受了2g头孢曲松剂量，在15分钟内静脉输注。在24小时的研究期间采集了14份静脉血样。通过超滤测定游离头孢曲松浓度。血浆和超滤液中的抗生素浓度通过离子对反相色谱法测量。使用非房室方法确定从总抗生素浓度和游离抗生素浓度得出的药代动力学参数。数据以中位数和范围表示。

结果

两组从总头孢曲松浓度得出的药代动力学参数相似，但患者稳态时校正分布容积中位数增加（P=0.05），达到0.18l/kg（范围0.11 - 0.29l/kg），而志愿者为0.15l/kg（范围0.13 - 0.22l/kg）。患者游离头孢曲松浓度 - 时间曲线下面积是志愿者的两倍（中位数192，范围114 - 301对中位数122，范围84 - 169h·mg⁻¹·l⁻¹；P = 0.03）。此外，患者体内游离头孢曲松浓度在更长时间内保持高于4mg/l（中位数16.7；范围12.6 - 21.4对中位数11.1；范围6.0 - 19.0h；P = 0.03）。