Getting the MAX out of Computational Models: The Prediction of Unbound-Brain and Unbound-Plasma Maximum Concentrations

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• 作者：Scot Mente ; Angela Doran ; Travis T. Wager
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：3
• 期：6
• 页码：515-519
• 全文大小：325K
• 年卷期：v.3,no.6(June 14, 2012)
• ISSN：1948-5875

文摘

The objective of this work was to establish that unbound maximum concentrations may be reasonably predicted from a combination of computed molecular properties assuming subcutaneous (SQ) dosing. Additionally, we show that the maximum unbound plasma and brain concentrations may be projected from a mixture of in vitro absorption, distribution, metabolism, excretion experimental parameters in combination with computed properties (volume of distribution, fraction unbound in microsomes). Finally, we demonstrate the utility of the underlying equations by showing that the maximum total plasma concentrations can be projected from the experimental parameters for a set of compounds with data collected from clinical research.

Keywords:

ADME; blood鈥揵rain barrier; brain availability; C_max; fraction unbound; volume of distribution