title: Consideration of the linear concentration increase of the unbound drug fraction in plasma.
abstract: The concentration of drug in plasma may not necessarily be much less than that of the drug binding proteins, as often considered. Thus the unbound drug fraction could be concentration dependent, which should be taken into account in the interpretation of drug pharmacokinetics and modeling. It is shown that the increase of the unbound drug fraction, f(u), can be very accurately considered proportional to the drug plasma concentration for a relatively wide range of concentrations. Equations for the calculation of f(u) in this linear range are obtained, as well the limiting drug concentration when the linear approximation of f(u) is applicable. The suggested approach greatly simplifies the calculation of f(u) and can be ready used in pharmacokinetic calculations and PK-PD models, as well as for the prediction of the change of f(u) due to the variation of protein concentrations in plasma. Naproxen protein binding in human plasma is considered as an illustration of the method.
authors.affiliation: Genetech Inc, South San Francisco, California 94080, USA. berezhkovskiy.leo@gene.com
authors.forename: Leonid M
authors.initials: LM
authors.lastname: Berezhkovskiy
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D016014:Linear Models; D008954:Models, Biological; D009288:Naproxen / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D009288:Naproxen