Investigation of the prerequisites for the optimization of specific plasma protein binding as a strategy for the reduction of first-pass hepatic metabolism.

1. It is hypothesized that the deliberate structural tailoring of compounds designed for drug use to increase the specific plasma protein binding can be used to reduce first-pass hepatic metabolism. To test the feasibility of this hypothesis, a dataset of drugs with plasma protein binding of 90% or above divided into three classes including 50 acids, 44 bases and 69 neutrals was analyzed. 2. Among the drugs with ≥99% plasma protein binding, the fraction of the total dose existing in free form in vivo (free dose fraction) decreased in the following order: acids (0.55%) > neutrals (0.16%) > bases (0.08%). The order was different for the fraction of the total dose that existed in plasma protein bound form (plasma protein bound dose fraction): acids (58%) > neutrals (17%) = bases (18%). 3. The free fraction was poorly correlated with the partition coefficient (Log P). The lower aqueous solubility associated with high plasma protein binding was explained by differences in Log P and not by the plasma protein binding per se. The logarithm of the extrarenal clearance was correlated with Log P. For acids and bases, extrarenal clearance was also correlated with fu. For neutrals, plasma protein binding had no protective effect.