P324 Effects of Protein Binding on Transporter Inhibitions

Qing Zhu , Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., Cambridge, MA
Mingxiang Liao , Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., Cambridge, MA
Bei-Ching Chuang , Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., Cambridge, MA
Suresh K. Balani , Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., Cambridge, MA
Cindy Xia , Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., Cambridge, MA
Transporter-mediated DDIs have drawn a lot of attention recently.  The International Transporter Consortium and FDA have provided some decision trees for the circumstances under which transporter studies need to be evaluated in the clinic.  In the suggested decision trees, the unbound maximum concentration at steady state has been proposed as [I]1,u for P-gp inhibition or uptake transporter inhibition. In the present study, we aimed at evaluating the effects of protein binding on transporter inhibitions for both efflux transporters and uptake transporters.  Ten P-gp inhibitors and 10 hepatic uptake transporter inhibitors (including OCT1 and OATP) were studied in the presence and absence of human plasma, using Caco-2 cells for P-gp inhibitor evaluations and human hepatocytes for hepatic uptake transporter inhibitor evaluations. Compared to the IC50 produced in protein free buffer, the IC50 did not change (shift <1.5 fold) in the presence of human plasma for the compounds which have protein binding less than 95%; but increased dramatically (shift > 2 fold) in the presence of human plasma for most of compounds which have protein binding more than 95%. The results suggested that one needs to be cautious when using [I]1,u/IC50 > 0.1 as a criteria for the need of a clinical DDI study.