Denk E, Hillegonds D, Vogel J, Synal A, Geppert C, Wendt K, Fattinger K, Hennessy C, Berglund M, Hurrell R F, Walczyk T
Laboratory of Human Nutrition, Institute of Food Science and Nutrition, ETH Zurich, Schmelzbergstrasse 7 (LFV D19.3), 8092, Zürich, Switzerland.
Anal Bioanal Chem. 2006 Nov;386(6):1587-602. doi: 10.1007/s00216-006-0795-5. Epub 2006 Oct 11.
Bone research is limited by the methods available for detecting changes in bone metabolism. While dual X-ray absorptiometry is rather insensitive, biochemical markers are subject to significant intra-individual variation. In the study presented here, we evaluated the isotopic labeling of bone using 41Ca, a long-lived radiotracer, as an alternative approach. After successful labeling of the skeleton, changes in the systematics of urinary 41Ca excretion are expected to directly reflect changes in bone Ca metabolism. A minute amount of 41Ca (100 nCi) was administered orally to 22 postmenopausal women. Kinetics of tracer excretion were assessed by monitoring changes in urinary 41Ca/40Ca isotope ratios up to 700 days post-dosing using accelerator mass spectrometry and resonance ionization mass spectrometry. Isotopic labeling of the skeleton was evaluated by two different approaches: (i) urinary 41Ca data were fitted to an established function consisting of an exponential term and a power law term for each individual; (ii) 41Ca data were analyzed by population pharmacokinetic (NONMEM) analysis to identify a compartmental model that describes urinary 41Ca tracer kinetics. A linear three-compartment model with a central compartment and two sequential peripheral compartments was found to best fit the 41Ca data. Fits based on the use of the combined exponential/power law function describing urinary tracer excretion showed substantially higher deviations between predicted and measured values than fits based on the compartmental modeling approach. By establishing the urinary 41Ca excretion pattern using data points up to day 500 and extrapolating these curves up to day 700, it was found that the calculated 41Ca/40Ca isotope ratios in urine were significantly lower than the observed 41Ca/40Ca isotope ratios for both techniques. Compartmental analysis can overcome this limitation. By identifying relative changes in transfer rates between compartments in response to an intervention, inaccuracies in the underlying model cancel out. Changes in tracer distribution between compartments were modeled based on identified kinetic parameters. While changes in bone formation and resorption can, in principle, be assessed by monitoring urinary 41Ca excretion over the first few weeks post-dosing, assessment of an intervention effect is more reliable approximately 150 days post-dosing when excreted tracer originates mainly from bone.
骨骼研究受到检测骨代谢变化可用方法的限制。双能X线吸收法相当不敏感，而生化标志物存在显著的个体内差异。在本文介绍的研究中，我们评估了使用长寿命放射性示踪剂41Ca对骨骼进行同位素标记作为一种替代方法。在成功标记骨骼后，预计尿中41Ca排泄系统的变化将直接反映骨钙代谢的变化。向22名绝经后女性口服微量的41Ca（100纳居里）。通过使用加速器质谱和共振电离质谱监测给药后长达700天尿中41Ca/40Ca同位素比值的变化，评估示踪剂排泄的动力学。通过两种不同方法评估骨骼的同位素标记：（i）将每个个体的尿41Ca数据拟合为一个由指数项和幂律项组成的既定函数；（ii）通过群体药代动力学（NONMEM）分析41Ca数据，以确定描述尿41Ca示踪剂动力学的房室模型。发现具有一个中央房室和两个连续外周房室的线性三室模型最适合41Ca数据。基于使用描述尿示踪剂排泄的组合指数/幂律函数的拟合显示，预测值与测量值之间的偏差显著高于基于房室建模方法的拟合。通过使用直至第500天的数据点建立尿41Ca排泄模式，并将这些曲线外推至第700天，发现两种技术计算出的尿中41Ca/40Ca同位素比值均显著低于观察到的41Ca/40Ca同位素比值。房室分析可以克服这一局限性。通过识别响应干预时房室之间转运速率的相对变化，基础模型中的不准确性相互抵消。基于确定的动力学参数对房室之间示踪剂分布的变化进行建模。虽然原则上可以通过监测给药后最初几周的尿41Ca排泄来评估骨形成和吸收的变化，但当排泄的示踪剂主要来自骨骼时，给药后约150天评估干预效果更为可靠。
