Plasma protein binding in drug discovery and development.
This review describes methods for quantifying the binding of small molecule drug candidates to plasma proteins and the application of these methods in drug discovery and development. Particular attention is devoted to methods amenable to medium-to-high throughput analysis and those well suited for measurement of compounds that are highly protein bound. The methods reviewed herein include the conventional techniques of equilibrium dialysis, ultrafiltration and ultracentrifugation, as well as some more novel approaches utilizing micropartitioning and biosensor-based analysis. Additional concepts that are discussed include plasma protein structure, enantioselective protein binding, drug displacement, the effect of patient demographics and disease states on free (unbound) drug levels, and the influence of protein binding on drug candidate pharmacokinetics and pharmacodynamics. Practical considerations pertaining to the evaluation of highly protein bound drug candidates are also highlighted.
Howard
Monique L
ML
Amgen Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
Hill
John J
JJ
Galluppi
Gerald R
GR
McLean
Matthew A
MA
D015374:Biosensing Techniques / Q000379:methods; D001798:Blood Proteins / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding
D001798:Blood Proteins; D004364:Pharmaceutical Preparations