2012
DOI: 10.1124/dmd.111.042994
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Mechanistic Pharmacokinetic Modeling for the Prediction of Transporter-Mediated Disposition in Humans from Sandwich Culture Human Hepatocyte Data

Abstract: ABSTRACT:With efforts to reduce cytochrome P450-mediated clearance (CL) during the early stages of drug discovery, transporter-mediated CL mechanisms are becoming more prevalent. However, the prediction of plasma concentration-time profiles for such compounds using physiologically based pharmacokinetic (PBPK) modeling is far less established in comparison with that for compounds with passively mediated pharmacokinetics (PK). In this study, we have assessed the predictability of human PK for seven organic anion… Show more

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Cited by 231 publications
(295 citation statements)
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“…The scaling factor obtained in rats between in vitro hepatic uptake and in vivo observation was applied to the model in order to predict the observed human PK. In the sandwich culture hepatocytes, the Cl int,T was determined to be 1.9 µL/min/million cell at 1 µM of pravastatin 8. When these in vitro data were directly used in the PBPK model, it failed to capture the curve of the time concentration profile of pravastatin administered intravenously 8, 9.…”
Section: Discussionmentioning
confidence: 99%
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“…The scaling factor obtained in rats between in vitro hepatic uptake and in vivo observation was applied to the model in order to predict the observed human PK. In the sandwich culture hepatocytes, the Cl int,T was determined to be 1.9 µL/min/million cell at 1 µM of pravastatin 8. When these in vitro data were directly used in the PBPK model, it failed to capture the curve of the time concentration profile of pravastatin administered intravenously 8, 9.…”
Section: Discussionmentioning
confidence: 99%
“…No additional scaling factor was applied for the prediction of uptake by the OATP transporter. The input for passive diffusion is 0.0001 mL/min/10 6 cells determined in sandwich culture hepatocytes 8. The canalicular efflux by MRP2 was described using a measured Cl int,T (1.2 µL/min/10 6 cells) in sandwich culture hepatocytes8 with a scaling factor of 0.18 9…”
Section: Methodsmentioning
confidence: 99%
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