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Research Article

Kinetic determinants of hepatic clearance: Plasma protein binding and hepatic uptake

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Pages 1110-1134 | Received 09 Jul 2007, Accepted 31 Aug 2007, Published online: 22 Sep 2008

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Crossref
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Crossref
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Crossref
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Joachim Bucher, Stephan Riedmaier, Anke Schnabel, Katrin Marcus, Gabriele Vacun, Thomas S Weiss, Wolfgang E Thasler, Andreas K Nüssler, Ulrich M Zanger & Matthias Reuss. (2011) A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes. BMC Systems Biology 5:1.
Crossref
Thomas R.B. Grandjean, Mike J. Chappell, James T.W. Yates, Kevin Jones, Gemma Wood & Tanya Coleman. (2011) Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein. Computer Methods and Programs in Biomedicine 104:2, pages 81-92.
Crossref
Leonid M. Berezhkovskiy. (2011) The influence of hepatic transport on the distribution volumes and mean residence time of drug in the body and the accuracy of estimating these parameters by the traditional pharmacokinetic calculations. Journal of Pharmaceutical Sciences 100:11, pages 5031-5047.
Crossref
Shahab Sheikh-Bahaei & C. Anthony Hunt. (2011) Enabling Clearance Predictions to Emerge from In Silico Actions of Quasi-Autonomous Hepatocyte Components. Drug Metabolism and Disposition 39:10, pages 1910-1920.
Crossref
Leonid M. Berezhkovskiy. (2011) The Corrected Traditional Equations for Calculation of Hepatic Clearance that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water and the Corresponding Corrected PBPK Equation. Journal of Pharmaceutical Sciences 100:3, pages 1167-1183.
Crossref
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David Hallifax, Joanne A. Foster & J. Brian Houston. (2010) Prediction of Human Metabolic Clearance from In Vitro Systems: Retrospective Analysis and Prospective View. Pharmaceutical Research 27:10, pages 2150-2161.
Crossref
Vikram Ramanathan & Nimish Vachharajani. 2009. Evaluation of Drug Candidates for Preclinical Development. Evaluation of Drug Candidates for Preclinical Development 135 167 .
Christopher J. Endres, Michael G. Endres & Jashvant D. Unadkat. (2009) Interplay of Drug Metabolism and Transport: A Real Phenomenon or an Artifact of the Site of Measurement?. Molecular Pharmaceutics 6:6, pages 1756-1765.
Crossref
K. A. CORTRIGHT, S. E. WETZLICH & A. L. CRAIGMILL. (2009) A PBPK model for midazolam in four avian species. Journal of Veterinary Pharmacology and Therapeutics 32:6, pages 552-565.
Crossref
John W. Nichols, Alex D. Hoffman & Patrick N. Fitzsimmons. (2009) Optimization of an isolated perfused rainbow trout liver model: Clearance studies with 7-ethoxycoumarin. Aquatic Toxicology 95:3, pages 182-194.
Crossref
Christopher Kohl. (2009) Transporters – The View from Industry. Chemistry & Biodiversity 6:11, pages 1988-1999.
Crossref
Masato Chiba, Yasuyuki Ishii & Yuichi Sugiyama. (2009) Prediction of Hepatic Clearance in Human From In Vitro Data for Successful Drug Development. The AAPS Journal 11:2.
Crossref
Mei-Ling Chen & Lawrence Yu. (2009) The Use of Drug Metabolism for Prediction of Intestinal Permeability. Molecular Pharmaceutics 6:1, pages 74-81.
Crossref
Thomas R.B. Grandjean, Mike J. Chappell, James T.W. Yates, Kevin Jones, Gemma Wood & Tanya Coleman. (2009) Compartmental Modelling of the Pharmacokinetics of a Breast Cancer Resistance Protein. IFAC Proceedings Volumes 42:12, pages 115-120.
Crossref
Masoud Jamei, Gemma L. Dickinson & Amin Rostami-Hodjegan. (2009) A Framework for Assessing Inter-individual Variability in Pharmacokinetics Using Virtual Human Populations and Integrating General Knowledge of Physical Chemistry, Biology, Anatomy, Physiology and Genetics: A Tale of ‘Bottom-Up’ vs ‘Top-Down’ Recognition of Covariates. Drug Metabolism and Pharmacokinetics 24:1, pages 53-75.
Crossref
Agnès Poirier, Thierry Lavé, Renée Portmann, Marie-Elise Brun, Frank Senner, Manfred Kansy, Hans-Peter Grimm & Christoph Funk. (2008) Design, Data Analysis, and Simulation of in Vitro Drug Transport Kinetic Experiments Using a Mechanistic in Vitro Model. Drug Metabolism and Disposition 36:12, pages 2434-2444.
Crossref

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