@article {Varmajpet.114.215970, author = {Manthena Varma and Yi-an Bi and Emi Kimoto and Jian Lin}, title = {Quantitative prediction of transporter- and enzyme-mediated clinical drug-drug interactions of OATP1B1 substrates using a mechanistic net-effect model}, elocation-id = {jpet.114.215970}, year = {2014}, doi = {10.1124/jpet.114.215970}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Quantitative prediction of complex drug-drug interactions (DDIs) involving hepatic transporters and Cytochrome P-450s (CYPs) is challenging. We evaluated the extent of DDIs of nine victim drugs - which are substrates to organic anion transporting polypeptide 1B1 and undergo CYP metabolism or biliary elimination - caused by five perpetrator drugs, using in vitro data and the proposed {\textquoteright}extended net-effect{\textquoteright} model. Hepatobiliary transport and metabolic clearance estimates were obtained from in vitro studies. Of the total of 62 clinical interaction combinations assessed using the net-effect model, 58 (94\%) could be predicted within a 2-fold error, with few false negative predictions. Model predictive performance improved significantly when in vitro active uptake clearance was corrected to recover in vivo clearance. The basic R-value model yielded only 63\% predictions within 2-fold error. This study demonstrates that the interactions involving transporter-enzyme interplay need to be mechanistically assessed for quantitative rationalization and prospective prediction.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2014/08/08/jpet.114.215970}, eprint = {https://jpet.aspetjournals.org/content/early/2014/08/08/jpet.114.215970.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }