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Title: Prediction of drug-drug interactions from in vitro data : impact of multiple inhibitors and inhibition mechanisms
Author: Hinton, Laura K.
ISNI:       0000 0001 3578 9820
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2008
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Predictions of drug-drug interactions (DDIs) rarely consider the effect of multiple inhibitors or multiple mechanisms of interaction. The gemfibrozil interactions involve inhibition ofCYF2C8 and the OATPIBI hepatic uptake transporter by both gemfibrozil and its acyl-glucuronide metabolite. The aim of this work was to assess the metabolic and transporter in vitro prediction models for their ability to predict complex DDIs as exemplified by gemfibrozil. In order to improve the general DDI prediction strategy, the impact of inhibition of intestinal metabolic enzymes was also investigated. Metabolic in vitro models were initially assessed for the prediction of gemfibrozil interactions using data collated from the literature. Prediction models incorporated both reversible inhibition of CYF2C8, CYF2C9 and CYF3A4 by gemfibrozil and time-dependent inhibition of CYF2C8 by gemfibrozilglucuronide. Additional in vitro work was performed to refine the input parameters for these models. ICso values for gemfibrozil and its glucuronide were obtained in human liver microsomes and hepatocytes using repaglinide and rosiglitazone as CYP2C8 probes. The glucuronide was 5 to 8-fold more potent towards CYF2C8 than the parent and the difference in ICso between microsomes and hepatocytes indicated an extensive accumulation of the inhibitors within the hepatocytes (up to 44-fold). Despite use of the refined data from this study in the prediction inodels, a general under-prediction trend remained. The potency of gemfibrozil and its glucuronide towards OATPIBI was assessed in a recombinant cell line expressing this transporter along with 12 other inhibitors. Gemfibrozil and its glucuronide showed comparable potency towards OATPIBI (ICso of 7.4 and 4.3IlM, respectively). Qualitative zoning of 14 DDIs mediated by gemfibrozil and the well-established OATPIBI inhibitor, cyclosporine, was carried out using the basic transporter model. The magnitude of observed gemfibrozil and cyclosporine DDIs was over-predicted by 17- and 34-fold, respectively. A refinement to the transporter model was proposed to incorporate the reliance ofa victim drug on the transporter for hepatic uptake (ft). The relative importance of the active uptake in comparison to the passive process was estimated for 4 drugs (repaglinide, rosiglitazone, atorvastatin and pravastatin) from experiments performed in the OATPIB1-expressing cell line and human hepatocytes (repaglinide). The ft values ranged from 0.5 to 0.8 and use of this data in the refined model significantly reduced the extent ofDDI over-prediction. The relative importance of intestinal metabolism in comparison to hepatic was investigated. Three methods for estimating the intestinal availability in the presence (Fo') and absence of an inhibitor (Fo) were assessed for a range ofCYF3A4 substrates. The assumption of maximal intestinal inhibition resulted in satisfactory predictions for most inhibitors and victim drugs indicating the use of this pragmatic approach in the DDI prediction strategy. Inhibition interactions via multiple mechanisms are a challenge to our ability to predict DDIs using in vitro data. A combined metabolic and transporter model is required to allow further refinement of the predictions
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available