Evaluation of highly bound drugs: interspecies, intersubject, and related comparisons

Free (unbound) drug is generally the pharmacologically relevant parameter for drug exposure. Thus, comparisons among species, among individuals, and in other situations such as cell culture or drug metabolism experiments in vitro should be based on free drug. Although the traditional focus has been on the absolute value for free drug, the applications for the data in this study are primarily comparative. Therefore, the authors evaluated direct dialysis of one plasma sample versus another. At equilibrium, the total concentration of valproate in human plasma was 3-fold higher than in rat plasma. The total concentration of monoacetyl dapsone was 10-fold higher in human plasma than in rat plasma and 18-fold higher in human plasma than in dog plasma. These results confirm predictions derived from conventional dialysis of each plasma sample separately versus buffer. These data can be interpreted directly, without interspecies correction factors for binding, especially for the most important cases--drugs that are highly protein-bound.