期刊
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
卷 109, 期 -, 页码 S83-S89出版社
ELSEVIER
DOI: 10.1016/j.ejps.2017.05.024
关键词
Binding kinetics; Rebinding; Distribution; Pharmacokinetics; Rate-limiting step; Diffusion
资金
- Innovative Medicines Initiative Joint Undertaking (IMI JU) [115366]
- European Union's Seventh Framework Programme
- European Federation of Pharmaceutical Industries and Associations (EFPIA)
The influence of drug-target binding kinetics on target occupancy can be influenced by drug distribution and diffusion around the target, often referred to as rebinding or diffusion-limited binding. This gives rise to a decreased decline of the drug-target complex concentration as a result of a locally higher drug concentration that arises around the target, which leads to prolonged target exposure to the drug. This phenomenon has been approximated by the steady-state approximation, assuming a steady-state concentration around the target. Recently, a rate-limiting step approximation of drug distribution and drug-target binding has been published. However, a comparison between both approaches has not been made so far. In this study, the rate-limiting step approximation has been rewritten into the same mathematical format as the steady-state approximation in order to compare the performance of both approaches for the investigation of the influence of drug-target binding kinetics on target occupancy. While both approximations clearly indicated the importance of k(on) and high target concentrations, it was shown that the rate-limiting step approximation is more accurate than the steady-state approximation, especially when dissociation is fast compared to association and distribution out of the binding compartment. It is therefore concluded that the new rate-limiting step approximation is to be preferred for assessing the influence of binding kinetics on local target site concentrations and target occupancy.
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