title: In vivo Target Residence Time and Kinetic Selectivity: The Association Rate Constant as Determinant.
abstract: 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.
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands.
authors.forename: Wilhelmus E A
authors.initials: WEA
authors.lastname: de Witte
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; Certara Quantitative Systems Pharmacology, Canterbury Innovation Centre, Canterbury CT2 7FG, UK.
authors.forename: Piet H
authors.initials: PH
authors.lastname: van der Graaf
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands. Electronic address: ecmdelange@lacdr.leidenuniv.nl.
authors.forename: Elizabeth C M
authors.initials: ECM
authors.lastname: de Lange
mesh_terms: D016503:Drug Delivery Systems; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008962:Models, Theoretical; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics
chemical_list: D004364:Pharmaceutical Preparations
keywords: association rate constant; in vivo; kinetic selectivity; pharmacokinetics; target binding kinetics; target-mediated drug disposition