Comment on the Article “Physiologically Based Modeling of Pravastatin Transporter-Mediated Hepatobiliary Disposition and Drug-Drug Interactions”
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To the Editor:
The ‘bottom-up’ prediction of transporter-based drug-drug interactions continues to be a challenge. In this context, we offer some comments on the recent publication of Varma et al. (2012) in this Journal (1). These authors describe the development of physiologically-based pharmacokinetic (PBPK) models to predict the kinetics of pravastatin and the impact of co-medication with cyclosporine, gemfibrozil or rifampicin. While the transporter-mediated interactions with gemfibrozil and rifampicin in healthy subjects were predicted within 20% by the dynamic models, that with cyclosporine as perpetrator was significantly underestimated.
In simulating the in vivodata for pravastatin given alone, it was necessary to fit the data using empirical scaling factors for hepatic sinusoidal uptake and canalicular efflux of 31 and 0.17, respectively. With regard to the second of these scaling factors, we suggest that there is prior experimental justification for the number, based on...
KeywordsCyclosporine Rifampicin Pravastatin Gemfibrozil Absolute Abundance
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