title: Pharmacokinetics and the drug-target residence time concept.
abstract: The concept of drug-target residence time has been in focus in recent drug discovery literature. However, few studies consider the combined effect of pharmacokinetics (PK) and binding kinetics (BK) on the duration of effect of a drug. Using a simple model that takes both PK and BK into account, we found that prolongation of binding owing to a long drug-target residence time can only occur when the binding dissociation is slower than the PK elimination. Data for several drugs and/or drug candidates in the literature indicate that the opposite is observed, that is, they have a slower elimination compared with dissociation. These observations greatly reduce the usability of drug-target residence times for estimating the duration of effect of a drug in vivo.
authors.affiliation: Department of Structure and Biophysics, AstraZeneca R&D, Pepparedsleden 1, 431 83 Mölndal, Sweden. goran.dahl@astrazeneca.com
authors.forename: Göran
authors.initials: G
authors.lastname: Dahl
authors.forename: Tomas
authors.initials: T
authors.lastname: Akerud
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000493:pharmacokinetics
chemical_list: D004364:Pharmaceutical Preparations; D011506:Proteins