Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination
Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination
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DOI：
10.1002/jps.20073
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发表时间：
2004-06-01
影响因子：
3.8
通讯作者：
Berezhkovskiy, LM
中科院分区：
文献类型：
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作者：
Berezhkovskiy, LM
考虑寻找具有外周药物消除的线性药代动力学系统的稳态分布容积 V-ss 的问题。常用方程 V-ss = (D/AUC)*MRT 仅适用于具有中枢（血浆）药物消除的系统。得到以下方程：V-ss = (D/AUC)*MRTint，其中AUC是静脉内(iv)推注药物剂量D后血浆中总药物浓度的时间曲线下通常计算的面积，MRTint是内在平均停留时间，即药物进入体循环(血浆)后在体内(系统)中花费的平均时间。如果发生外周药物流出，则无法从静脉推注药物输入后的药物血浆浓度曲线中找到 MRTint 值。获得的方程不包含血浆和器官中蛋白质和组织结合的即时平衡的假设，因此包含所有可能反应的速率。如果药物仅通过中央室（血浆）离开系统，并且血浆中结合和未结合的药物部分之间存在即时平衡，则 MRTint 等于 MRT = AUMC/AUC，这是使用静脉推注后血浆中总药物浓度的时间过程计算的。因此，如果满足该方程有效性的假设，则获得的方程与传统方程一致，V-ss = (D/AUC)*MRT。考虑了确定稳态分布容积和 MRTint 的实验方法，以及确定是否发生外周药物消除的问题。得到了考虑外周消除的组织-血浆分配系数的计算方程。讨论了传统计算的 V-ss = (D/AUC)*MRT 与 (D/AUC)*MRTint 给出的真实值之间的差异。 (C) 2004 Wiley-Liss, Inc. 和美国药剂师协会。
The problem of finding the steady-state volume of distribution V-ss for a linear pharmacokinetic system with peripheral drug elimination is considered. A commonly used equation V-ss = (D/AUC)*MRT is applicable only for the systems with central (plasma) drug elimination. The following equation, V-ss = (D/AUC)*MRTint, was obtained, where AUC is the commonly calculated area under the time curve of the total drug concentration in plasma after intravenous (iv) administration of bolus drug dose, D, and MRTint is the intrinsic mean residence time, which is the average time the drug spends in the body (system) after entering the systemic circulation (plasma). The value of MRTint cannot be found from a drug plasma concentration profile after an iv bolus drug input if a peripheral drug exit occurs. The obtained equation does not contain the assumption of an immediate equilibrium of protein and tissue binding in plasma and organs, and thus incorporates the rates of all possible reactions. If drug exits the system only through central compartment (plasma) and there is an instant equilibrium between bound and unbound drug fractions in plasma, then MRTint becomes equal to MRT = AUMC/AUC, which is calculated using the time course of the total drug concentration in plasma after an iv bolus injection. Thus, the obtained equation coincides with the traditional one, V-ss = (D/AUC)*MRT, if the assumptions for validity of this equation are met. Experimental methods for determining the steady-state volume of distribution and MRTint, as well as the problem of determining whether peripheral drug elimination occurs, are considered. The equation for calculation of the tissue-plasma partition coefficient with the account of peripheral elimination is obtained. The difference between traditionally calculated V-ss = (D/AUC)*MRT and the true value given by (D/AUC)*MRTint is discussed. (C) 2004 Wiley-Liss, Inc. and the American Pharmacists Association.