RT Journal Article
SR Electronic
T1 Rapid Identification of P-glycoprotein Substrates and Inhibitors
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1976
OP 1984
DO 10.1124/dmd.106.012351
VO 34
IS 12
A1 Cheng Chang
A1 Praveen M. Bahadduri
A1 James E. Polli
A1 Peter W. Swaan
A1 Sean Ekins
YR 2006
UL http://dmd.aspetjournals.org/content/34/12/1976.abstract
AB Identifying molecules that interact with P-glycoprotein (P-gp) is important for drug discovery but is also generally reliant on time-consuming in vitro and in vivo studies. As an alternative approach, the current study applied pharmacophore models and database screening to rapidly retrieve molecules that bind as substrates or inhibitors for P-gp from commercial databases and then confirmed their affinity as inhibitors in vitro. Seven molecules (acitretin, cholecalciferol, misoprostol, nafcillin, repaglinide, salmeterol, and telmisartan) with no published details for P-gp affinity, one positive control inhibitor (miconazole), and two negative control molecules (phenelzine and zonisamide) were selected for testing. The MDCK-MDR1 in vitro cell model was used to confirm their inhibitory effect on [3H]digoxin transport, and the ATPase assay was used as an additional in vitro tool to indicate P-gp activation. All seven test drugs were confirmed to have P-gp affinity. Additionally, our experimental results provided plausible explanations for the published pharmacokinetic profiles of the tested drugs and their classification according to the biopharmaceutics and drug disposition classification system. In this study, we showed the successful application of pharmacophore models to accurately predict P-gp binding, which holds promise to anticipate drug-drug interactions from screening drug databases and a priori prediction of novel P-gp inhibitors or substrates. The American Society for Pharmacology and Experimental Therapeutics