健康老年人的药物肾脏处理。肌酐清除率会低估肾功能，而药代动力学实际上保持不变。

Renal handling of drugs in the healthy elderly. Creatinine clearance underestimates renal function and pharmacokinetics remain virtually unchanged.

作者信息

Fliser D, Bischoff I, Hanses A, Block S, Joest M, Ritz E, Mutschler E

机构信息

Department of Internal Medicine, Ruperto-Carola University, Heidelberg, Germany.

出版信息

Eur J Clin Pharmacol. 1999 May;55(3):205-11. doi: 10.1007/s002280050619.

DOI:10.1007/s002280050619

PMID:10379636

Abstract

OBJECTIVE

It is commonly assumed that renal function, and in parallel the excretion of drugs, is considerably reduced in the elderly. Endogenous creatinine clearance or indirect estimates of this parameter are generally recommended for adapting drug dosage. The present study evaluates the validity of both assumptions.

METHODS

We compared pharmacokinetics (and pharmacodynamics) of 50 mg atenolol, 800 mg piracetam and 25 mg hydrochlorothiazide plus 50 mg triamterene in ten healthy young [25 (2) years] and 11 healthy elderly subjects [68 (5) years]. Inulin (Cin) and para-aminohippurate [PAH (CPAH)] clearance (infusion clearance technique), endogenous (C(Cr)) and calculated (Cockroft-Gault) creatinine clearance, analysis of drugs and their metabolites (HPLC), were performed. Renal haemodynamics and the pharmacokinetics of beta-adrenergic blocking agent, diuretics and the nootropic agent piracetam, respectively, were measured on separate days.

RESULTS

Cin was significantly (P < 0.01) lower in the healthy elderly subjects [104 (12) vs 120 (14) ml x min(-2) x 1.73 m(-2) in the young], but remained within the normal range (> 90 ml x min(-2) x 1.73 m(-2)). In contrast, C(Cr) was even lower in healthy elderly subjects [95 (24) vs 121 (20) ml x min(-1) in the young], and the Cockroft-Gault clearance underestimated true glomerular filtration rate (GFR) even more seriously [74 (17) vs 122 (16) ml min(-1)]. For atenolol the mean area under the curve (AUC) was similar in both groups [3.16 (0.48) microg x h(-1) x ml(-1) in the elderly vs 3.01 (0.30) in the young], as was the mean maximal plasma concentration [0.42 (0.07) vs 0.44 (0.06) microg x ml(-1)], but the proportion of the drug excreted in urine was marginally (P < 0.025) lower in the elderly. Similar results were obtained for hydrochlorothiazide, whereas no marked differences between the groups were found for triamterene and its metabolite. Furthermore, the pharmacodynamic action of diuretics was not significantly altered in the elderly.

CONCLUSIONS

The true GFR of the healthy elderly remains within the normal range and is underestimated by creatinine clearance and more so by its surrogate (Cockroft-Gault clearance). In parallel, pharmacokinetics of renally excreted drugs are not affected in the healthy elderly to a clinically significant extent. For drugs with a narrow therapeutic window, indirect estimates of GFR appear to be an unreliable means for calculating correct dosage in the elderly.

摘要

目的

人们通常认为老年人的肾功能以及与之并行的药物排泄功能会大幅下降。一般建议采用内生肌酐清除率或该参数的间接估计值来调整药物剂量。本研究评估了这两种假设的有效性。

方法

我们比较了10名健康年轻受试者[25（2）岁]和11名健康老年受试者[68（5）岁]服用50mg阿替洛尔、800mg吡拉西坦以及25mg氢氯噻嗪加50mg氨苯蝶啶后的药代动力学（和药效动力学）情况。采用菊粉（Cin）和对氨基马尿酸[PAH（CPAH）]清除率（输注清除技术）、内生（C（Cr））和计算得出的（Cockcroft-Gault）肌酐清除率、药物及其代谢产物分析（高效液相色谱法）。分别在不同日期测量肾脏血流动力学以及β-肾上腺素能阻滞剂、利尿剂和促智药吡拉西坦的药代动力学。

结果

健康老年受试者的Cin显著更低（P<0.01）[年轻受试者为120（14）ml·min⁻²·1.73m⁻²，老年受试者为104（12）ml·min⁻²·1.73m⁻²]，但仍在正常范围内（>90ml·min⁻²·1.73m⁻²）。相比之下，健康老年受试者的C（Cr）更低[年轻受试者为121（20）ml·min⁻¹，老年受试者为95（24）ml·min⁻¹]，且Cockcroft-Gault清除率对真实肾小球滤过率（GFR）的低估更为严重[分别为74（17）ml·min⁻¹和122（16）ml·min⁻¹]。对于阿替洛尔，两组的平均曲线下面积（AUC）相似[老年组为3.16（0.48）μg·h⁻¹·ml⁻¹，年轻组为3.01（0.30）μg·h⁻¹·ml⁻¹]，平均最大血浆浓度也相似[分别为0.42（0.07）μg·ml⁻¹和0.44（0.06）μg·ml⁻¹]，但老年组药物经尿液排泄的比例略低（P<0.025）。氢氯噻嗪也得到了类似结果，而氨苯蝶啶及其代谢产物在两组间未发现明显差异。此外，利尿剂的药效动力学作用在老年人中未发生显著改变。