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Abstract
Knowledge regarding unbound concentrations is of vital importance when exploring the PK and PD of a drug. The accurate and reproducible determination of plasma protein binding and unbound concentrations for a compound/drug is a serious challenge for the bioanalytical laboratory. When the drug is in equilibrium with the binding protein(s), this equilibrium will shift when physiological conditions are not met. Furthermore, the true unbound fraction/concentration is unknown, and there are numerous publications in the scientific literature reporting and discussing data that have been produced without sufficient control of the parameters influencing the equilibrium. In this Review, different parameters affecting the equilibrium and analysis are discussed, together with suggestions on how to control these parameters in order to produce as trustworthy results for unbound concentrations/fractions as possible.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Acknowledgements
The experiments referred to in this review were performed at AstraZeneca R&D, Södertälje, Sweden. M Bath, A Bogstedt and MAL Eriksson are acknowledged for performing many of these experiments. Many thanks to J Gabrielsson, for a lot of interesting discussions on unbound concentrations and their role in drug discovery and development, and to D Westerlund for reviewing the manuscript.