Prediction of CYP3A Mediated Drug-Drug Interactions Using Human Hepatocytes Suspended in Human Plasma
Drug Metabolism & Disposition
Pharmacy and Pharmaceutical Sciences
Cryopreserved human hepatocytes suspended in human plasma (HHSHP) represent an integrated metabolic environment for predicting drug-drug interactions (DDIs). In this study, 13 CYP3A reversible and/or time dependent inhibitors (TDI) were incubated with HHSHP for 20 min over a range of concentrations after which midazolam 1'-hydroxylation was used to measure CYP3A activity. This single incubation time method yielded IC50 values for the 13 inhibitors. For each CYP3A inhibitor/victim drug pair, the IC50 value was combined with total average plasma concentration of the inhibitor in humans, fraction of the victim drug cleared by CYP3A and intestinal availability of the victim drug to predict the ratio of plasma area under the curve of the victim drug in the presence and absence of inhibitor. Of 52 clinical DDI studies utilizing these 13 inhibitors identified in the literature, 85% were predicted by this method within 2-fold of the observed change and all were predicted within 3-fold. Subsequent studies to determine mechanism (reversible and TDI) were performed by using a range of incubation periods and inhibitor concentrations. This system differentiated between reversible inhibitors, TDIs and the combination of both. When the reversible and inactivation parameters were incorporated into predictive models, 65% of 52 clinical DDIs were predicted within 2-fold of the observed changes and 88% were within 3-fold. Thus HHSHP produced accurate DDI predictions with a simple IC50 determined at a single incubation time regardless of the inhibition mechanism, further if needed, the mechanism(s) of inhibition can be identified.
Mao J, Mohutsky MA, Harrelson JP, Wrighton SA, Hall SD. Prediction of CYP3A Mediated Drug-Drug Interactions Using Human Hepatocytes Suspended in Human Plasma. Drug Metab Dispos. 2011 Jan 6. [Epub ahead of print]