Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Parathyroid Hormone-Calcium Homeostasis in Rats and Humans
Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Parathyroid Hormone-Calcium Homeostasis in Rats and Humans
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DOI：
10.1124/jpet.109.152033
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发表时间：
2009-07-01
影响因子：
3.5
通讯作者：
Maurer, Tristan S.
中科院分区：
文献类型：
--
作者：
Abraham, Anson K.;Mager, Donald E.;Maurer, Tristan S.
本研究的目的是建立一个基于机理的药代动力学/药效学模型，描述大鼠和人甲状旁腺激素(PTH)-钙离子系统的调节。内源性甲状旁腺激素和钙离子的时间浓度数据来自于大鼠(正常成年男性)和人类的文献。此外，采用颈静脉插管给雄性SD大鼠皮下注射外源性甲状旁腺素，并随时间测量其血药浓度。建立了内源性甲状旁腺素、钙离子和外源性甲状旁腺素浓度的数学模型，并对模型进行了同时拟合。Ca~(2+)浓度用周转模型描述，其耗竭是由络合剂引起的，PTH浓度用前体依赖的间接反应模型表征。同样的结构模型被用来拟合在人体中获得的数据。甲状旁腺激素的刺激是由钙敏感受体的占据所驱动的，生理钙离子浓度的降低增加了甲状旁腺素的分泌，甲状旁腺素的变化可以用该模型来充分描述。大鼠和人的甲状旁腺素刺激能力呈基线依赖性[S-最大_大鼠=34.8x PTHO]和人[S-最大_人=392/PTHO]。模拟结果表明，正常大鼠对钙离子诱导的甲状旁腺素刺激的敏感度是人类的两倍。总之，所开发的模型充分表征了甲状旁腺素-钙离子跨物种的调节，并可能在针对该系统的治疗药物的开发中有用。
The purpose of this study was to develop a mechanism-based pharmacokinetic/pharmacodynamic model that describes the regulation of the parathyroid hormone (PTH)-Ca2+ system in rats and humans. Temporal concentration data for endogenous PTH and Ca2+ were extracted from literature for rats (normal adult males) and humans. In addition, exogenous PTH was administered subcutaneously to male Sprague-Dawley rats with jugular vein catheters, and plasma concentrations were measured over time. A mathematical model was developed and fitted simultaneously to endogenous PTH, Ca2+, and exogenous PTH concentrations in rats. Ca2+ concentrations were described using a turnover model, with its depletion being induced by a chelating agent, and PTH concentrations were characterized using a precursor-dependent indirect response model. The same structural model was used for fitting data obtained in humans. PTH stimulation was driven by occupancy of the Ca2+ sensing receptor, and lowering of physiological Ca2+ concentrations increased PTH secretion, with PTH profiles being adequately described by the model. PTH stimulatory capacity was baseline-dependent in rats [S-max_rats = 34.8 x PTHo] and humans [S-max_humans = 392/PTHo]. Modeling results suggest that normal rats are twice as sensitive to Ca2+-induced PTH stimulation compared with humans. In conclusion, the developed model adequately characterizes the PTH-Ca2+ regulation across species and may be useful in the development of therapeutic drugs targeting this system.