Berezhkovskiy Leonid M
Genetech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
J Pharm Sci. 2007 Dec;96(12):3432-43. doi: 10.1002/jps.20986.
A problem of substantial delay in reaching the steady state drug concentration in particular organ (compartment) compared to the time of reaching the steady state plasma concentration is considered. It is shown that the ratio of the terminal (V(beta)) and the steady state (V(ss)) volumes of distribution, V(beta)/V(ss), appears to be an indication of possible lag in reaching the steady state in the organ tissue compared to plasma. The estimations of the time of reaching the steady state drug concentration in the organ are suggested. The in vivo based pharmacokinetic model, which uses the experimentally measured drug plasma concentration time course and the appropriate equation for the kinetics of drug distribution into the tissues, is suggested. It is intended to determine the kinetic mechanism of drug distribution into the tissues. The model was applied to interpret the kinetics of drug distribution into the brain. The importance of precise measurement of drug plasma concentration at terminal phase for obtaining accurate values of V(beta) and V(ss) is emphasized: this allows predicting a possible slow plasma-tissue drug transfer and substantial difference in time of reaching the steady state by the body and plasma.
考虑到与达到稳态血浆浓度的时间相比，在特定器官（房室）中达到稳态药物浓度存在显著延迟的问题。结果表明，终末分布容积（Vβ）与稳态分布容积（Vss）之比Vβ/Vss似乎表明与血浆相比，器官组织达到稳态可能存在滞后。建议对器官中达到稳态药物浓度的时间进行估算。提出了一种基于体内的药代动力学模型，该模型使用实验测量的药物血浆浓度时间过程以及药物向组织分布动力学的适当方程，旨在确定药物向组织分布的动力学机制。该模型被用于解释药物向脑内分布的动力学。强调了在终末阶段精确测量药物血浆浓度对于获得准确的Vβ和Vss值的重要性：这有助于预测可能缓慢的血浆-组织药物转运以及机体和血浆达到稳态时间的显著差异。
