RT Journal Article
SR Electronic
T1 PREDICTION OF DRUG-DRUG INTERACTIONS FROM IN VITRO INDUCTION DATA
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1971
OP 1974
DO 10.1124/dmd.108.021907
VO 36
IS 9
A1 Odette A. Fahmi
A1 Sherri Boldt
A1 Mary Kish
A1 R. Scott Obach
A1 Larry M. Tremaine
YR 2008
UL http://dmd.aspetjournals.org/content/36/9/1971.abstract
AB Cytochrome P450 induction-mediated drug-drug interaction (DDI) is one of the major concerns in clinical practice and for the pharmaceutical industry. Previously, a novel approach [the relative induction score (RIS)] was developed using the Fa2N-4 immortalized human hepatocyte line and proposed as a tool for predicting magnitude of clinical DDIs caused by induction of CYP3A. The approach is based on combining in vitro induction parameters (EC50 and Emax) with the efficacious free plasma concentrations to calculate a relative induction score, which is correlated to the magnitude of clinical DDI for midazolam or ethinyl estradiol. To expand the applicability of the RIS model, we have measured induction caused by ten drugs in two different lots of human cryopreserved hepatocytes and correlated the data to clinical DDIs using the RIS. The results demonstrated that, as with Fa2N-4 hepatocytes, sigmoidal relationships can be derived between RIS and magnitude of induction of midazolam and ethinyl estradiol clearance in cryopreserved human hepatocytes. This study demonstrates the general applicability of the relative induction score approach using the human cryopreserved hepatocyte model to predict clinical DDI. The American Society for Pharmacology and Experimental Therapeutics