Assessment of serum protein binding to predict non-specific uptake in vivo

Pros, cons & Future potential

By screening beforehand a panel of drugs on their serum protein binding, the number of preselected molecules that need to be evaluated in vivo can be reduced as these will exhibit in vivo non-specific binding, in particular liver accumulation. Depending on the application, this can lead to undesired toxic side-effects and decrease the bioavailability of the drug.

To differentiate the signal of the drug from the signal of the serum proteins, the drug needs to be labeled either with a fluorophore or a radioisotope. One should be aware that the modification of a drug can also impact the biodistribution profile. In particular, hydrophobic fluorescent dyes are known to exhibit non-specific protein binding. Moreover, one should be reminded that the in vitro assay is a static assay that does not necessarily reflect the dynamic process happening in vivo and that metabolization, clearance, compartimentalization etc is not taken into account. Moreover, this assay does not predict in vivo efficacy of the compounds.

This method could be adapted to screen the binding of drugs to other types of proteins that can predict non-specific accumulation in certain undesired organs/tissues in the body.

This method could be used to screen additional types of drugs (small molecules, peptides, large antibodies) for their non-specific serum protein binding and as such predict their in vivo behavior. This will limit the number of compounds tested in vivo.