同时给予一组标志物以测定肾脏药物消除途径：氟康唑与菊粉、对氨基马尿酸和吲哚洛尔之间不存在药代动力学相互作用。
Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol.
作者信息
Gross A S, McLachlan A J, Minns I, Beal J B, Tett S E
机构信息
Department of Clinical Pharmacology, Royal North Shore Hospital, Sydney, Australia.
出版信息
Br J Clin Pharmacol. 2001 Jun;51(6):547-55. doi: 10.1046/j.1365-2125.2001.01390.x.
AIMS
Previous studies suggest that estimated creatinine clearance, the conventional measure of renal function, does not adequately reflect changes in renal drug handling in some patients, including the immunosuppressed. The aim of this study was to develop and validate a cocktail of markers, to be given in a single administration, capable of detecting alterations in the renal elimination pathways of glomerular filtration, tubular secretion and tubular reabsorption.
METHODS
Healthy male subjects (n = 12) received intravenously infused 2500 mg sinistrin (glomerular filtration) and 440 mg p-aminohippuric acid (PAH; anion secretion), and orally administered 100 mg fluconazole (reabsorption) and 15 mg rac-pindolol (cation secretion). The potential interaction between these markers was investigated in a pharmacokinetic study where markers (M) or fluconazole (F) were administered alone or together (M + F). Validated analytical methods were used to measure plasma and urine concentrations in order to quantify the renal handling of each marker. Plasma protein binding of fluconazole was measured by ultrafiltration. All subjects had an estimated creatinine clearance within the normal range. The renal clearance of each marker (mean+/- s.d.) was calculated as the ratio of the amount excreted in urine and the area-under-the-concentration-time curve. Statistical comparisons were made using a paired t-test and 95% confidence intervals were reported.
RESULTS
The renal clearances of sinistrin (M: 119 +/- 31 ml min(-1); M + F: 130 +/- 40 ml min(-1); P = 0.32), PAH (M: 469 +/- 145 ml min(-1); M + F: 467 +/- 146 ml min(-1); P = 0.95), R-pindolol (M: 204 +/- 41 ml min(-1); M + F: 190 +/- 41 ml min(-1); P = 0.39; n = 11), S-pindolol (M: 225 +/- 55 ml min(-1); M + F: 209 +/- 60 ml min(-1); P = 0.27; n = 11) and fluconazole (F: 14.9 +/- 3.8 ml min(-1); M + F: 13.6 +/- 3.4 ml min(-1); P = 0.16) were similar when the markers or fluconazole were administered alone (M or F) or as a cocktail (M + F).
CONCLUSIONS
This study found no interaction between markers and fluconazole in healthy male subjects, suggesting that a single administration of this cocktail of markers of different renal processes can be used to simultaneously investigate pathways of renal drug elimination.
目的
以往研究表明，估算的肌酐清除率作为肾功能的传统指标，在包括免疫抑制患者在内的部分患者中不能充分反映肾脏药物处理的变化。本研究的目的是研发并验证一种单次给药的标志物组合，能够检测肾小球滤过、肾小管分泌和肾小管重吸收等肾脏排泄途径的改变。
方法
健康男性受试者（n = 12）静脉输注2500 mg 左聚糖酐（用于肾小球滤过）和440 mg 对氨基马尿酸（PAH；用于阴离子分泌），并口服100 mg 氟康唑（用于重吸收）和15 mg 消旋吲哚洛尔（用于阳离子分泌）。在一项药代动力学研究中，单独或联合（M + F）给予标志物（M）或氟康唑（F），研究这些标志物之间的潜在相互作用。采用经过验证的分析方法测量血浆和尿液浓度，以量化每种标志物的肾脏处理情况。通过超滤法测量氟康唑的血浆蛋白结合率。所有受试者的估算肌酐清除率均在正常范围内。每种标志物的肾脏清除率（均值±标准差）通过尿液排泄量与浓度-时间曲线下面积的比值计算得出。采用配对t检验进行统计学比较，并报告95%置信区间。
结果
单独给予标志物（M）或氟康唑（F）或作为组合给予（M + F）时，左聚糖酐的肾脏清除率（M：119 ± 31 ml·min⁻¹；M + F：130 ± 40 ml·min⁻¹；P = 0.32）、PAH（M：469 ± 145 ml·min⁻¹；M + F：467 ± 146 ml·min⁻¹；P = 0.95）、R-吲哚洛尔（M：204 ± 41 ml·min⁻¹；M + F：190 ± 41 ml·min⁻¹；P = 0.39；n = 11）、S-吲哚洛尔（M：225 ± 55 ml·min⁻¹；M + F：209 ± 60 ml·min⁻¹；P = 0.27；n = 11）和氟康唑（F：14.9 ± 3.8 ml·min⁻¹；M + F：13.6 ± 3.4 ml·min⁻¹；P = 0.16）相似。
结论
本研究发现健康男性受试者中标志物与氟康唑之间无相互作用，这表明单次给予这种不同肾脏过程的标志物组合可用于同时研究肾脏药物排泄途径。
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