In vivo Target Residence Time and Kinetic Selectivity: The Association Rate Constant as Determinant

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• 作者：Wilhelmus E.A. de Witte¹ ; Meindert Danhof¹ ; Piet H. van der Graaf¹ ; ² ; Elizabeth C.M. de Lange¹ ; ^{ecmdelange@lacdr.leidenuniv.nl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：pharmacokinetics ; target binding kinetics ; kinetic selectivity ; in vivo ; association rate constant ; target-mediated drug disposition
• 刊名：Trends in Pharmacological Sciences
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：37
• 期：10
• 页码：831-842
• 全文大小：2708 K

文摘

It is generally accepted that, in conjunction with pharmacokinetics, the first-order rate constant of target dissociation is a major determinant of the time course and duration of in vivo target occupancy. Here we show that the second-order rate constant of target association can be equally important. On the basis of the commonly used mathematical models for drug–target binding, it is shown that a high target association rate constant can increase the (local) concentration of the drug, which decreases the rate of decline of target occupancy. The increased drug concentration can also lead to increased off-target binding and decreased selectivity. Therefore, the kinetics of both target association and dissociation need to be taken into account in the selection of drug candidates with optimal pharmacodynamic properties.