分配量
药代动力学
分布(数学)
化学
稳态(化学)
配送量
内科学
药理学
生物
医学
数学
数学分析
物理化学
作者
Masahiro Yahata,Yuji Ishii,Takeshi Nakagawa,Takao Watanabe,Izuru Miyawaki
摘要
Abstract This study aimed to investigate the applicability of the Øie‐Tozer model to predict human distribution volume (Vd) in the central compartment (V 1 ), Vd at steady state (Vd ss ), and Vd at beta phase (Vd β ) based on animal Vd. Twenty compounds that have a human V 1 /Vd ss of 0.053–0.66 were selected from the literature. After intravenous administration of the compounds at 0.1 mg/kg to rats, dogs, and monkeys, plasma concentrations were determined, and pharmacokinetic parameters were obtained by one/two‐compartmental analyses. The human V 1 , Vd ss , and Vd β were predicted from animal Vd using the Øie‐Tozer model, and the predictability was compared with that using proportionality and simple allometry. The Øie‐Tozer model was the most reliable method for the overall prediction of Vd and applicable for accurately predicting human V 1 , Vd ss , and Vd β (89%, 85%, and 68% of the compounds within a 3‐fold error, respectively) when data of monkey for V 1 and data of three animal species for Vd ss and Vd β were used. Additionally, the predicted human Vd with the two‐compartment model was applicable for predicting pharmacokinetic profiles/parameters in humans after intravenous administration of 18 compounds [except for valproic acid (monophasic elimination profile) and chlorpromazine (deviation: Vd ss < V 1 )]. The prediction was more accurate than that using the predicted Vd ss with the one‐compartment model (e.g., underestimation of maximum plasma concentrations: 2 vs 8 compounds within a 3‐fold error, respectively). In summary, the Øie‐Tozer model was applicable for predicting human V 1 , Vd ss , and Vd β , and their predicted Vd with the two‐compartment model can lead to accurate pharmacokinetic prediction of compounds that show biphasic elimination.
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