Free drug principle

Plasma Protein Binding and the Free Drug Principle Recent Developments and Applications... 

A similar strategy was employed to identify a DPP-IV inhibitor (6) with good in vivo potency in a mouse model of diabetes [44], Plasma protein binding, as assessed by shift assay (50% serum), was presented for all final compounds. The compound selected as having the best overall profile was active in vivo at 0.1 mg/kg. The activity at 1 h post-dose was consistent with the free drug principle - total plasma concentration 269 nM murine-free fraction 4% unbound plasma concentration 11 nM in vitro potency versus murine DPP-IV 6nM. 

Intracellular targets can present a more complex situation with respect to the application of the free drug principle. The unavailability of reliable general methods for determining free drug concentrations inside the cell (as opposed to total drug associated with the cell, which can usually be measured), often renders... 

Exceptions to the free drug principle refer to situations where the unbound drug levels in a pharmacologically relevant compartment cannot be easily rationalized or target occupancy does not appear to be driven by unbound drug levels. In most such cases, the discrepancies relate to non-steady-state behavior or reflect the action of an energy-driven transport phenomenon. A number of such real or apparent exceptions have been cataloged in a recent review [3]. 

Examination of apparent exceptions to the free drug principle is important because such studies can lead to the identification of new processes that may be important for understanding drug action in certain circumstances. 

For more about plasma protein binding and the free drug principle, see Trainor, G.L. The importance of plasma protein binding in drug discovery. Expert Opin. Drug Discovery 2007, 2, 51-64, and Trainor,... 

G.L. Plasma Protein Binding and the Free Drug Principle Recent Developments and Applications , Chapter 31 in Annual Reports in Medicinal Chemistry, Volume 42, Macor, J.E., Ed. (San Diego, Academic Press, 2007). 

---