@article {Elsbydmd.118.083832, author = {Robert Elsby and Victoria Hare and Hannah Neal and Samuel Outteridge and Catherine Pearson and Katie Plant and Rachel Upcott Gill and Philip Butler and Robert J Riley}, title = {Mechanistic in vitro studies indicate that the clinical drug-drug interaction between telithromycin and simvastatin acid is driven by time-dependent inhibition of CYP3A4 with minimal effect on OATP1B1}, elocation-id = {dmd.118.083832}, year = {2018}, doi = {10.1124/dmd.118.083832}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {A previous attempt to accurately quantify the increased simvastatin acid exposure due to drug-drug interaction (DDI) with coadministered telithromycin, using a mechanistic static model, substantially underpredicted the magnitude of area under the plasma concentration-time curve ratio (AUCR) based on reversible inhibition of cytochrome P450 (CYP) 3A4 and organic anion transporting polypeptide (OATP) 1B1 (Elsby et al., 2012). In order to reconcile this disconnect between predicted and clinically observed AUCR, telithromycin was evaluated as a time-dependent inhibitor of CYP3A4 in vitro, as well as an inhibitor of OATP1B1. Telithromycin inhibited OATP1B1-mediated [3H]-estradiol 17β-D-glucuronide (0.02 μM) transport with a mean IC50 of 12.0{\textpm}1.45 μM and was determined by IC50 shift and kinetic analyses to be a mixed reversible inhibitor of CYP3A4-mediated midazolam 1-hydroxylation with a mean Ki of 3.65{\textpm}0.531 μM. The 2.83-fold shift in IC50 (10.4 μM to 3.68 μM) following a 30-min metabolic pre-incubation confirmed telithromycin as a time-dependent inhibitor of CYP3A4; determined mean KI and kinact values for inactivation being 1.05{\textpm}0.226 μM and 0.02772{\textpm}0.00272 min-1, respectively. Following integration of an enzyme time-dependent inhibition component into the previous mechanistic static model using the in vitro inhibitory kinetic parameters determined above, the newly predicted simvastatin acid AUCR (10.8 or 5.4) resulting from perturbation of its critical disposition pathways matched the clinically observed AUCR (10.8 or 4.3) following co-administration, or staggered administration, with telithromycin, respectively. These results indicate time-dependent inhibition of CYP3A4 by telithromycin as the primary driver underlying its clinical DDI with simvastatin acid.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2018/10/22/dmd.118.083832}, eprint = {https://dmd.aspetjournals.org/content/early/2018/10/22/dmd.118.083832.full.pdf}, journal = {Drug Metabolism and Disposition} }