{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T13:13:51Z","timestamp":1768050831258,"version":"3.49.0"},"reference-count":83,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The individual character of pharmacokinetics is of great importance in the risk assessment of new drug leads in pharmacological research. Amongst others, it is severely influenced by the properties and inter-individual variability of the enzymes and transporters of the drug detoxification system of the liver. Predicting individual drug biotransformation capacity requires quantitative and detailed models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this contribution we present the<jats:italic>de novo<\/jats:italic>deterministic modeling of atorvastatin biotransformation based on comprehensive published knowledge on involved metabolic and transport pathways as well as physicochemical properties. The model was evaluated on primary human hepatocytes and parameter identifiability analysis was performed under multiple experimental constraints. Dynamic simulations of atorvastatin biotransformation considering the inter-individual variability of the two major involved enzymes CYP3A4 and UGT1A3 based on quantitative protein expression data in a large human liver bank (n = 150) highlighted the variability in the individual biotransformation profiles and therefore also points to the individuality of pharmacokinetics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A dynamic model for the biotransformation of atorvastatin has been developed using quantitative metabolite measurements in primary human hepatocytes. The model comprises kinetics for transport processes and metabolic enzymes as well as population liver expression data allowing us to assess the impact of inter-individual variability of concentrations of key proteins. Application of computational tools for parameter sensitivity analysis enabled us to considerably improve the validity of the model and to create a consistent framework for precise computer-aided simulations in toxicology.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1752-0509-5-66","type":"journal-article","created":{"date-parts":[[2011,5,6]],"date-time":"2011-05-06T18:31:29Z","timestamp":1304706689000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes"],"prefix":"10.1186","volume":"5","author":[{"given":"Joachim","family":"Bucher","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Riedmaier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anke","family":"Schnabel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Marcus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Vacun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas S","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang E","family":"Thasler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas K","family":"N\u00fcssler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich M","family":"Zanger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Reuss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2011,5,6]]},"reference":[{"key":"662_CR1","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/S1359-6446(03)02971-4","volume":"9","author":"A Bugrim","year":"2004","unstructured":"Bugrim A, Nikolskaya T, Nikolsky Y: Early prediction of drug metabolism and toxicity: systems biology approach and modeling. Drug Discovery Today. 2004, 9: 127-135. 10.1016\/S1359-6446(03)02971-4","journal-title":"Drug Discovery Today"},{"key":"662_CR2","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/nrd1032","volume":"2","author":"H van de Waterbeemd","year":"2003","unstructured":"van de Waterbeemd H, Gifford E: ADMET in silico modelling: Towards prediction paradise?. Nature Reviews Drug Discovery. 2003, 2: 192-204. 10.1038\/nrd1032","journal-title":"Nature Reviews Drug Discovery"},{"key":"662_CR3","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1038\/nrd2378","volume":"6","author":"JA Kramer","year":"2007","unstructured":"Kramer JA, Sagartz JE, Morris DL: The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates. Nat Rev Drug Discov. 2007, 6: 636-649. 10.1038\/nrd2378","journal-title":"Nat Rev Drug Discov"},{"key":"662_CR4","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1016\/j.drudis.2006.07.001","volume":"11","author":"W Huisinga","year":"2006","unstructured":"Huisinga W, Telgmann R, Wulkow M: The virtual laboratory approach to pharmacokinetics: design principles and concepts. Drug Discovery Today. 2006, 11: 800-805. 10.1016\/j.drudis.2006.07.001","journal-title":"Drug Discovery Today"},{"key":"662_CR5","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1126\/science.1069492","volume":"295","author":"H Kitano","year":"2002","unstructured":"Kitano H: Systems biology: a brief overview. Science. 2002, 295: 1662-1664. 10.1126\/science.1069492","journal-title":"Science"},{"key":"662_CR6","doi-asserted-by":"publisher","first-page":"A938","DOI":"10.1289\/ehp.112-a938","volume":"112","author":"A Spivey","year":"2004","unstructured":"Spivey A: Systems biology - The big picture. Environmental Health Perspectives. 2004, 112: A938-A943.","journal-title":"Environmental Health Perspectives"},{"key":"662_CR7","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1124\/dmd.32.7.715","volume":"32","author":"TB Andersson","year":"2004","unstructured":"Andersson TB, Bredberg E, Ericsson H, Sjoberg H: An evaluation of the in vitro metabolism data for predicting the clearance and drug-drug interaction potential of CYP2C9 substrates. Drug Metabolism and Disposition. 2004, 32: 715-721. 10.1124\/dmd.32.7.715","journal-title":"Drug Metabolism and Disposition"},{"key":"662_CR8","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1080\/00498250110057350","volume":"31","author":"SE Clarke","year":"2001","unstructured":"Clarke SE, Jeffrey P: Utility of metabolic stability screening: comparison of in vitro and in vivo clearance. Xenobiotica. 2001, 31: 591-598. 10.1080\/00498250110057350","journal-title":"Xenobiotica"},{"key":"662_CR9","doi-asserted-by":"publisher","first-page":"305","DOI":"10.2174\/1389200003338947","volume":"1","author":"JH Lin","year":"2000","unstructured":"Lin JH: Sense and nonsense in the prediction of drug-drug interactions. Current Drug Metabolism. 2000, 1: 305-331. 10.2174\/1389200003338947","journal-title":"Current Drug Metabolism"},{"key":"662_CR10","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/S0169-409X(02)00009-1","volume":"54","author":"MJ de Groot","year":"2002","unstructured":"de Groot MJ, Ekins S: Pharmacophore modeling of cytochromes P450. Advanced Drug Delivery Reviews. 2002, 54: 367-383. 10.1016\/S0169-409X(02)00009-1","journal-title":"Advanced Drug Delivery Reviews"},{"key":"662_CR11","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1071\/CH06140","volume":"59","author":"J Gasteiger","year":"2006","unstructured":"Gasteiger J, Reitz M, Han YQ, Sacher O: Analyzing biochemical pathways using neural networks and genetic algorithms. Australian Journal of Chemistry. 2006, 59: 854-858. 10.1071\/CH06140.","journal-title":"Australian Journal of Chemistry"},{"key":"662_CR12","doi-asserted-by":"publisher","first-page":"3631","DOI":"10.1021\/jm030102a","volume":"46","author":"D Korolev","year":"2003","unstructured":"Korolev D, Balakin KV, Nikolsky Y, Kirillov E, Ivanenkov YA, Savchuk NP, Ivashchenko AA, Nikolskaya T: Modeling of human cytochrome P450-mediated drug metabolism using unsupervised machine learning approach. Journal of Medicinal Chemistry. 2003, 46: 3631-3643. 10.1021\/jm030102a","journal-title":"Journal of Medicinal Chemistry"},{"key":"662_CR13","doi-asserted-by":"publisher","first-page":"709","DOI":"10.3109\/03602539808996328","volume":"30","author":"DFV Lewis","year":"1998","unstructured":"Lewis DFV, Ioannides C, Parke DV: An improved and updated version of the compact procedure for the evaluation of P450-mediated chemical activation. Drug Metabolism Reviews. 1998, 30: 709-737. 10.3109\/03602539808996328","journal-title":"Drug Metabolism Reviews"},{"key":"662_CR14","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/S1383-5718(97)00145-9","volume":"412","author":"DFV Lewis","year":"1998","unstructured":"Lewis DFV, Ioannides C, Parke DV: Further evaluation of COMPACT, the molecular orbital approach for the prospective safety evaluation of chemicals. Mutation Research-Genetic Toxicology and Environmental Mutagenesis. 1998, 412: 41-54. 10.1016\/S1383-5718(97)00145-9","journal-title":"Mutation Research-Genetic Toxicology and Environmental Mutagenesis"},{"key":"662_CR15","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.1021\/ci700010t","volume":"47","author":"L Terfloth","year":"2007","unstructured":"Terfloth L, Bienfait B, Gasteiger J: Ligand-based models for the isoform specificity of cytochrome P450 3A4, 2D6, and 2C9 substrates. Journal of Chemical Information and Modeling. 2007, 47: 1688-1701. 10.1021\/ci700010t","journal-title":"Journal of Chemical Information and Modeling"},{"key":"662_CR16","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/S0169-409X(02)00007-8","volume":"54","author":"EY Zhang","year":"2002","unstructured":"Zhang EY, Phelps MA, Cheng C, Ekins S, Swaan PW: Modeling of active transport systems. Advanced Drug Delivery Reviews. 2002, 54: 329-354. 10.1016\/S0169-409X(02)00007-8","journal-title":"Advanced Drug Delivery Reviews"},{"key":"662_CR17","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1124\/dmd.30.1.96","volume":"30","author":"S Ekins","year":"2002","unstructured":"Ekins S, Erickson JA: A pharmacophore for human pregnane X receptor ligands. Drug Metabolism and Disposition. 2002, 30: 96-99. 10.1124\/dmd.30.1.96","journal-title":"Drug Metabolism and Disposition"},{"key":"662_CR18","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.1023\/A:1021429105173","volume":"19","author":"S Ekins","year":"2002","unstructured":"Ekins S, Mirny L, Schuetz EG: A ligand-based approach to understanding selectivity of nuclear hormone receptors PXR, CAR, FXR, LXR alpha, and LXR beta. Pharmaceutical Research. 2002, 19: 1788-1800. 10.1023\/A:1021429105173","journal-title":"Pharmaceutical Research"},{"key":"662_CR19","doi-asserted-by":"publisher","first-page":"2408","DOI":"10.1021\/ci7002076","volume":"47","author":"TJ Hou","year":"2007","unstructured":"Hou TJ, Wang JM, Li YY: ADME evaluation in drug discovery. 8. The prediction of human intestinal absorption by a support vector machine. Journal of Chemical Information and Modeling. 2007, 47: 2408-2415. 10.1021\/ci7002076","journal-title":"Journal of Chemical Information and Modeling"},{"key":"662_CR20","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1021\/ci6003515","volume":"47","author":"TJ Hou","year":"2007","unstructured":"Hou TJ, Wang JM, Zhang W, Xu XJ: ADME evaluation in drug discovery. 6. Can oral bioavailability in humans be effectively predicted by simple molecular property-based rules?. Journal of Chemical Information and Modeling. 2007, 47: 460-463. 10.1021\/ci6003515","journal-title":"Journal of Chemical Information and Modeling"},{"key":"662_CR21","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1021\/ci049884m","volume":"44","author":"TJ Hou","year":"2004","unstructured":"Hou TJ, Zhang W, Xia K, Qiao XB, Xu XJ: ADME evaluation in drug discovery. 5. Correlation of Caco-2 permeation with simple molecular properties. Journal of Chemical Information and Computer Sciences. 2004, 44: 1585-1600.","journal-title":"Journal of Chemical Information and Computer Sciences"},{"key":"662_CR22","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1002\/qsar.200510161","volume":"25","author":"JT Leonard","year":"2006","unstructured":"Leonard JT, Roy K: On selection of training and test sets for the development of predictive QSAR models. Qsar & Combinatorial Science. 2006, 25: 235-251. 10.1002\/qsar.200510161","journal-title":"Qsar & Combinatorial Science"},{"key":"662_CR23","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1038\/nrd2173","volume":"6","author":"A Rostami-Hodjegan","year":"2007","unstructured":"Rostami-Hodjegan A, Tucker GT: Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nature Reviews Drug Discovery. 2007, 6: 140-148. 10.1038\/nrd2173","journal-title":"Nature Reviews Drug Discovery"},{"key":"662_CR24","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/0378-4274(95)03355-O","volume":"79","author":"ME Andersen","year":"1995","unstructured":"Andersen ME: Development of Physiologically-Based Pharmacokinetic and Physiologically-Based Pharmacodynamic Models for Applications in Toxicology and Risk Assessment. Toxicology Letters. 1995, 79: 35-44. 10.1016\/0378-4274(95)03355-O","journal-title":"Toxicology Letters"},{"key":"662_CR25","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1002\/jps.2600721003","volume":"72","author":"LE Gerlowski","year":"1983","unstructured":"Gerlowski LE, Jain RK: Physiologically Based Pharmacokinetic Modeling - Principles and Applications. Journal of Pharmaceutical Sciences. 1983, 72: 1103-1127. 10.1002\/jps.2600721003","journal-title":"Journal of Pharmaceutical Sciences"},{"key":"662_CR26","doi-asserted-by":"publisher","DOI":"10.1002\/0471478768","volume-title":"Phyiologically Based Pharmacokinetic Modelling","author":"M Reddy","year":"2005","unstructured":"Reddy M, Yang RS, Andersen ME, Clewell I, H J: Phyiologically Based Pharmacokinetic Modelling. 2005, John Wiley & Sons,"},{"key":"662_CR27","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1080\/10937400701724337","volume":"11","author":"CM Thompson","year":"2008","unstructured":"Thompson CM, Sonawane B, Barton HA, DeWoskin RS, Lipscomb JC, Schlosser P, Chiu WA, Krishnan K: Approaches for applications of physiologically based pharmacokinetic models in risk assessment. Journal of Toxicology and Environmental Health-Part B-Critical Reviews. 2008, 11: 519-547. 10.1080\/10937400701724337.","journal-title":"Journal of Toxicology and Environmental Health-Part B-Critical Reviews"},{"key":"662_CR28","volume-title":"Biosilico","author":"S Willmann","year":"2003","unstructured":"Willmann S, Lippert J, Sevestre M, Solodenko J, Fois F, Schmitt W: PK-Sim\u00ae: a physiologically based pharmacokinetic 'whole-body' model. Biosilico. 2003, 1:"},{"key":"662_CR29","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.2174\/156802605774297038","volume":"5","author":"SK Balani","year":"2005","unstructured":"Balani SK, Miwa GT, Gan LS, Wu JT, Lee FW: Strategy of utilizing in vitro and in vivo ADME tools for lead optimization and drug candidate selection. Current Topics in Medicinal Chemistry. 2005, 5: 1033-1038. 10.2174\/156802605774297038","journal-title":"Current Topics in Medicinal Chemistry"},{"key":"662_CR30","doi-asserted-by":"publisher","first-page":"847","DOI":"10.2174\/138920008786485092","volume":"9","author":"CECA Hop","year":"2008","unstructured":"Hop CECA, Cole MJ, Davidson RE, Duignan DB, Federico J, Janiszewski JS, Jenkins K, Krueger S, Lebowitz R, Liston TE, Mitchell W, Snyder M, Steyn SJ, Soglia JR, Taylor C, Troutman MD, Umland J, West M, Whalen KM, Zelesky V, Zhao SX: High Throughput ADME Screening: Practical Considerations, Impact on the Portfolio and Enabler of In Silico ADME Models. Current Drug Metabolism. 2008, 9: 847-853. 10.2174\/138920008786485092","journal-title":"Current Drug Metabolism"},{"key":"662_CR31","doi-asserted-by":"publisher","first-page":"165","DOI":"10.2174\/138920006775541552","volume":"7","author":"SS Singh","year":"2006","unstructured":"Singh SS: Preclinical pharmacokinetics: An approach towards safer and efficacious drugs. Current Drug Metabolism. 2006, 7: 165-182. 10.2174\/138920006775541552","journal-title":"Current Drug Metabolism"},{"key":"662_CR32","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1517\/17425255.3.2.235","volume":"3","author":"I Nestorov","year":"2007","unstructured":"Nestorov I: Whole-body physiologically based pharmacokinetic models. Expert Opinion on Drug Metabolism & Toxicology. 2007, 3: 235-249. 10.1517\/17425255.3.2.235","journal-title":"Expert Opinion on Drug Metabolism & Toxicology"},{"key":"662_CR33","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1080\/00498250701658296","volume":"37","author":"M Baker","year":"2007","unstructured":"Baker M, Parton T: Kinetic determinants of hepatic clearance: plasma protein binding and hepatic uptake. Xenobiotica. 2007, 37: 1110-1134. 10.1080\/00498250701658296","journal-title":"Xenobiotica"},{"key":"662_CR34","doi-asserted-by":"publisher","first-page":"2434","DOI":"10.1124\/dmd.108.020750","volume":"36","author":"A Poirier","year":"2008","unstructured":"Poirier A, Lave T, Portmann R, Brun ME, Senner F, Kansy M, Grimm HP, Funk C: Design, Data Analysis, and Simulation of in Vitro Drug Transport Kinetic Experiments Using a Mechanistic in Vitro Model. Drug Metabolism and Disposition. 2008, 36: 2434-2444. 10.1124\/dmd.108.020750","journal-title":"Drug Metabolism and Disposition"},{"key":"662_CR35","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1124\/dmd.107.019455","volume":"36","author":"SW Paine","year":"2008","unstructured":"Paine SW, Parker AJ, Gardiner P, Webborn PJH, Riley RJ: Prediction of the pharmacokinetics of atorvastatin, cerivastatin, and indomethacin using kinetic models applied to isolated rat hepatocytes. Drug Metabolism and Disposition. 2008, 36: 1365-1374. 10.1124\/dmd.107.019455","journal-title":"Drug Metabolism and Disposition"},{"key":"662_CR36","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1023\/A:1026392429112","volume":"4","author":"WE Thasler","year":"2003","unstructured":"Thasler WE, Weiss TS, Schillhorn K, Stoll PT, Irrgang B, Jauch KW: Charitable State-Controlled Foundation Human Tissue and Cell Research: Ethic and Legal Aspects in the Supply of Surgically Removed Human Tissue For Research in the Academic and Commercial Sector in Germany. Cell Tissue Bank. 2003, 4: 49-56. 10.1023\/A:1026392429112","journal-title":"Cell Tissue Bank"},{"key":"662_CR37","volume-title":"Strategies in Regenerative Medicine","author":"AK Nussler","year":"2008","unstructured":"Nussler AK, Nussler NC, Merk V, Brulport M, Schormann W, Yao P, Hengstler JG: The Holy grail of hepatocyte culturing and therapeutic use. Strategies in Regenerative Medicine. Edited by: Santin M. 2008, New York: Springer,"},{"key":"662_CR38","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1038\/clpt.2009.181","volume":"87","author":"S Riedmaier","year":"2009","unstructured":"Riedmaier S, Klein K, Hofmann U, Keskitalo JE, Neuvonen PJ, Schwab M, Niemi M, Zanger UM: UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo. Clin Pharmacol Ther. 2009, 87: 65-73.","journal-title":"Clin Pharmacol Ther"},{"key":"662_CR39","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1002\/hep.1840380424","volume":"38","author":"R Wolbold","year":"2003","unstructured":"Wolbold R, Klein K, Burk O, Nussler AK, Neuhaus P, Eichelbaum M, Schwab M, Zanger UM: Sex is a major determinant of CYP3A4 expression in human liver. Hepatology. 2003, 38: 978-988.","journal-title":"Hepatology"},{"key":"662_CR40","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.1002\/pmic.200800680","volume":"9","author":"E Langenfeld","year":"2009","unstructured":"Langenfeld E, Zanger UM, Jung K, Meyer HE, Marcus K: Mass spectrometry-based absolute quantification of microsomal cytochrome P450 2D6 in human liver. Proteomics. 2009, 9: 2313-2323. 10.1002\/pmic.200800680","journal-title":"Proteomics"},{"key":"662_CR41","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1124\/dmd.107.015230","volume":"35","author":"TC Goosen","year":"2007","unstructured":"Goosen TC, Bauman JN, Davis JA, Yu C, Hurst SI, Williams JA, Loi CM: Atorvastatin glucuronidation is minimally and nonselectively inhibited by the fibrates gemfibrozil, fenofibrate, and fenofibric acid. Drug Metab Dispos. 2007, 35: 1315-1324. 10.1124\/dmd.107.015230","journal-title":"Drug Metab Dispos"},{"key":"662_CR42","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1124\/dmd.30.5.505","volume":"30","author":"T Prueksaritanont","year":"2002","unstructured":"Prueksaritanont T, Subramanian R, Fang X, Ma B, Qiu Y, Lin JH, Pearson PG, Baillie TA: Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos. 2002, 30: 505-512. 10.1124\/dmd.30.5.505","journal-title":"Drug Metab Dispos"},{"key":"662_CR43","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1023\/A:1018923325359","volume":"10","author":"AS Kearney","year":"1993","unstructured":"Kearney AS, Crawford LF, Mehta SC, Radebaugh GW: The interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxyacid forms of the HMG-CoA reductase inhibitor, CI-981. Pharm Res. 1993, 10: 1461-1465. 10.1023\/A:1018923325359","journal-title":"Pharm Res"},{"key":"662_CR44","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1007\/978-1-60327-517-0_20","volume":"477","author":"M Aviram","year":"2008","unstructured":"Aviram M, Rosenblat M: Paraoxonases (PON1, PON2, PON3) analyses in vitro and in vivo in relation to cardiovascular diseases. Methods Mol Biol. 2008, 477: 259-276. 10.1007\/978-1-60327-517-0_20","journal-title":"Methods Mol Biol"},{"key":"662_CR45","doi-asserted-by":"publisher","first-page":"33435","DOI":"10.1074\/jbc.M004543200","volume":"275","author":"DI Draganov","year":"2000","unstructured":"Draganov DI, Stetson PL, Watson CE, Billecke SS, La Du BN: Rabbit serum paraoxonase 3 (PON3) is a high density lipoprotein-associated lactonase and protects low density lipoprotein against oxidation. J Biol Chem. 2000, 275: 33435-33442. 10.1074\/jbc.M004543200","journal-title":"J Biol Chem"},{"key":"662_CR46","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1194\/jlr.M400511-JLR200","volume":"46","author":"DI Draganov","year":"2005","unstructured":"Draganov DI, Teiber JF, Speelman A, Osawa Y, Sunahara R, La Du BN: Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res. 2005, 46: 1239-1247. 10.1194\/jlr.M400511-JLR200","journal-title":"J Lipid Res"},{"key":"662_CR47","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1124\/mol.63.4.945","volume":"63","author":"C Gouedard","year":"2003","unstructured":"Gouedard C, Koum-Besson N, Barouki R, Morel Y: Opposite regulation of the human paraoxonase-1 gene PON-1 by fenofibrate and statins. Mol Pharmacol. 2003, 63: 945-956. 10.1124\/mol.63.4.945","journal-title":"Mol Pharmacol"},{"key":"662_CR48","doi-asserted-by":"publisher","first-page":"6371","DOI":"10.1021\/bi047440d","volume":"44","author":"O Khersonsky","year":"2005","unstructured":"Khersonsky O, Tawfik DS: Structure-reactivity studies of serum paraoxonase PON1 suggest that its native activity is lactonase. Biochemistry. 2005, 44: 6371-6382. 10.1021\/bi047440d","journal-title":"Biochemistry"},{"key":"662_CR49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0163-7258(98)00016-3","volume":"80","author":"U Christians","year":"1998","unstructured":"Christians U, Jacobsen W, Floren LC: Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar?. Pharmacol Ther. 1998, 80: 1-34. 10.1016\/S0163-7258(98)00016-3","journal-title":"Pharmacol Ther"},{"key":"662_CR50","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1016\/S0090-9556(24)15086-6","volume":"28","author":"W Jacobsen","year":"2000","unstructured":"Jacobsen W, Kuhn B, Soldner A, Kirchner G, Sewing KF, Kollman PA, Benet LZ, Christians U: Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. Drug Metab Dispos. 2000, 28: 1369-1378.","journal-title":"Drug Metab Dispos"},{"key":"662_CR51","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1080\/00498250400015319","volume":"34","author":"H Fujino","year":"2004","unstructured":"Fujino H, Saito T, Tsunenari Y, Kojima J, Sakaeda T: Metabolic properties of the acid and lactone forms of HMG-CoA reductase inhibitors. Xenobiotica. 2004, 34: 961-971. 10.1080\/00498250400015319","journal-title":"Xenobiotica"},{"key":"662_CR52","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1080\/00498250802334391","volume":"38","author":"JE Park","year":"2008","unstructured":"Park JE, Kim KB, Bae SK, Moon BS, Liu KH, Shin JG: Contribution of cytochrome P450 3A4 and 3A5 to the metabolism of atorvastatin. Xenobiotica. 2008, 38: 1240-1251. 10.1080\/00498250802334391","journal-title":"Xenobiotica"},{"key":"662_CR53","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/j.clpt.2006.09.010","volume":"80","author":"M Grube","year":"2006","unstructured":"Grube M, Kock K, Oswald S, Draber K, Meissner K, Eckel L, Bohm M, Felix SB, Vogelgesang S, Jedlitschky G, Siegmund W, Warzok R, Kroemer HK: Organic anion transporting polypeptide 2B1 is a high-affinity transporter for atorvastatin and is expressed in the human heart. Clinical Pharmacology & Therapeutics. 2006, 80: 607-620. 10.1016\/j.clpt.2006.09.010","journal-title":"Clinical Pharmacology & Therapeutics"},{"key":"662_CR54","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/sj.clpt.6100038","volume":"81","author":"YY Lau","year":"2007","unstructured":"Lau YY, Huang Y, Frassetto L, Benet LZ: effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2007, 81: 194-204. 10.1038\/sj.clpt.6100038","journal-title":"Clin Pharmacol Ther"},{"key":"662_CR55","doi-asserted-by":"publisher","first-page":"452","DOI":"10.2133\/dmpk.20.452","volume":"20","author":"M Nishimura","year":"2005","unstructured":"Nishimura M, Naito S: Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet. 2005, 20: 452-477. 10.2133\/dmpk.20.452","journal-title":"Drug Metab Pharmacokinet"},{"key":"662_CR56","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1161\/CIRCRESAHA.109.203596","volume":"106","author":"MJ Knauer","year":"2010","unstructured":"Knauer MJ, Urquhart BL, Meyer zu Schwabedissen HE, Schwarz UI, Lemke CJ, Leake BF, Kim RB, Tirona RG: Human skeletal muscle drug transporters determine local exposure and toxicity of statins. Circ Res. 2010, 106: 297-306. 10.1161\/CIRCRESAHA.109.203596","journal-title":"Circ Res"},{"key":"662_CR57","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1124\/dmd.107.014902","volume":"35","author":"C Hilgendorf","year":"2007","unstructured":"Hilgendorf C, Ahlin G, Seithel A, Artursson P, Ungell AL, Karlsson J: Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines. Drug Metabolism and Disposition. 2007, 35: 1333-1340. 10.1124\/dmd.107.014902","journal-title":"Drug Metabolism and Disposition"},{"key":"662_CR58","doi-asserted-by":"publisher","first-page":"16184","DOI":"10.1074\/jbc.273.26.16184","volume":"273","author":"L Li","year":"1998","unstructured":"Li L, Lee TK, Meier PJ, Ballatori N: Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter. J Biol Chem. 1998, 273: 16184-16191. 10.1074\/jbc.273.26.16184","journal-title":"J Biol Chem"},{"key":"662_CR59","doi-asserted-by":"publisher","first-page":"G271","DOI":"10.1152\/ajpgi.00075.2007","volume":"293","author":"C Mahagita","year":"2007","unstructured":"Mahagita C, Grassl SM, Piyachaturawat P, Ballatori N: Human organic anion transporter 1B1 and 1B3 function as bidirectional carriers and do not mediate GSH-bile acid cotransport. Am J Physiol Gastrointest Liver Physiol. 2007, 293: G271-278. 10.1152\/ajpgi.00075.2007","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"662_CR60","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1124\/dmd.108.020834","volume":"36","author":"PJ Kilford","year":"2008","unstructured":"Kilford PJ, Gertz M, Houston JB, Galetin A: Hepatocellular binding of drugs: Correction for unbound fraction in hepatocyte incubations using microsomal binding or drug lipophilicity data. Drug Metabolism and Disposition. 2008, 36: 1194-1197. 10.1124\/dmd.108.020834","journal-title":"Drug Metabolism and Disposition"},{"key":"662_CR61","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1038\/sj.bjp.0703920","volume":"132","author":"K Bogman","year":"2001","unstructured":"Bogman K, Peyer AK, Torok M, Kusters E, Drewe J: HMG-CoA reductase inhibitors and P-glycoprotein modulation. Br J Pharmacol. 2001, 132: 1183-1192. 10.1038\/sj.bjp.0703920","journal-title":"Br J Pharmacol"},{"key":"662_CR62","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1177\/00912700022008612","volume":"40","author":"RA Boyd","year":"2000","unstructured":"Boyd RA, Stern RH, Stewart BH, Wu X, Reyner EL, Zegarac EA, Randinitis EJ, Whitfield L: Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol. 2000, 40: 91-98. 10.1177\/00912700022008612","journal-title":"J Clin Pharmacol"},{"key":"662_CR63","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1124\/dmd.104.002477","volume":"33","author":"C Chen","year":"2005","unstructured":"Chen C, Mireles RJ, Campbell SD, Lin J, Mills JB, Xu JJ, Smolarek TA: Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos. 2005, 33: 537-546. 10.1124\/dmd.104.002477","journal-title":"Drug Metab Dispos"},{"key":"662_CR64","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1023\/B:PHAM.0000041466.84653.8c","volume":"21","author":"JH Hochman","year":"2004","unstructured":"Hochman JH, Pudvah N, Qiu J, Yamazaki M, Tang C, Lin JH, Prueksaritanont T: Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin. Pharm Res. 2004, 21: 1686-1691.","journal-title":"Pharm Res"},{"key":"662_CR65","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1007\/s11095-005-9371-5","volume":"23","author":"T Sakaeda","year":"2006","unstructured":"Sakaeda T, Fujino H, Komoto C, Kakumoto M, Jin JS, Iwaki K, Nishiguchi K, Nakamura T, Okamura N, Okumura K: Effects of acid and lactone forms of eight HMG-CoA reductase inhibitors on CYP-mediated metabolism and MDR1-mediated transport. Pharmaceutical Research. 2006, 23: 506-512. 10.1007\/s11095-005-9371-5","journal-title":"Pharmaceutical Research"},{"key":"662_CR66","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1023\/B:PHAM.0000026420.79421.8f","volume":"21","author":"P Chandra","year":"2004","unstructured":"Chandra P, Brouwer KLR: The complexities of hepatic drug transport: Current knowledge and emerging concepts. Pharmaceutical Research. 2004, 21: 719-735.","journal-title":"Pharmaceutical Research"},{"key":"662_CR67","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/S0165-6147(97)01147-4","volume":"19","author":"BA Hamelin","year":"1998","unstructured":"Hamelin BA, Turgeon J: Hydrophilicity\/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends in Pharmacological Sciences. 1998, 19: 26-37. 10.1016\/S0165-6147(97)01147-4","journal-title":"Trends in Pharmacological Sciences"},{"key":"662_CR68","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1124\/dmd.104.002436","volume":"33","author":"RP Austin","year":"2005","unstructured":"Austin RP, Barton P, Mohmed S, Riley RJ: The binding of drugs to hepatocytes and its relationship to physicochemical properties. Drug Metab Dispos. 2005, 33: 419-425.","journal-title":"Drug Metab Dispos"},{"key":"662_CR69","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1124\/dmd.106.010413","volume":"34","author":"D Hallifax","year":"2006","unstructured":"Hallifax D, Houston JB: Uptake and intracellular binding of lipophilic amine drugs by isolated rat hepatocytes and implications for prediction of in vivo metabolic clearance. Drug Metab Dispos. 2006, 34: 1829-1836. 10.1124\/dmd.106.010413","journal-title":"Drug Metab Dispos"},{"key":"662_CR70","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1089\/ten.2006.0071","volume":"13","author":"R Schwartlander","year":"2007","unstructured":"Schwartlander R, Schmid J, Brandenburg B, Katenz E, Wolfgang F, Vondran R, Pless G, Cheng XD, Pascher A, Neuhaus P, Sauer IM: Continuously microscopically observed and process-controlled cell culture within the SlideReactor: Proof of a new concept for cell characterization. Tissue Engineering. 2007, 13: 187-196. 10.1089\/ten.2006.0071","journal-title":"Tissue Engineering"},{"key":"662_CR71","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1046\/j.1365-2885.2002.00442.x","volume":"25","author":"PL Toutain","year":"2002","unstructured":"Toutain PL, Bousquet-Melou A: Free drug fraction vs free drug concentration: a matter of frequent confusion. J Vet Pharmacol Ther. 2002, 25: 460-463. 10.1046\/j.1365-2885.2002.00442.x","journal-title":"J Vet Pharmacol Ther"},{"key":"662_CR72","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1124\/dmd.107.015636","volume":"35","author":"K Bartholome","year":"2007","unstructured":"Bartholome K, Rius M, Letschert K, Keller D, Timmer J, Keppler D: Data-based mathematical modeling of vectorial transport across double-transfected polarized cells. Drug Metab Dispos. 2007, 35: 1476-1481. 10.1124\/dmd.107.015636","journal-title":"Drug Metab Dispos"},{"key":"662_CR73","first-page":"312","volume-title":"Proceedings of the Genetic and Evolutionary Computation Conference (GECCO-2001); Washington, D.C., USA","author":"J Poland","year":"2001","unstructured":"Poland J, Zell A: Main Vector Adaptation: A CMA Variant with Linear Time and Space Complexity. Proceedings of the Genetic and Evolutionary Computation Conference (GECCO-2001); Washington, D.C., USA. 2001, 312-317."},{"key":"662_CR74","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1007\/BF01400352","volume":"51","author":"P Deuflhard","year":"1987","unstructured":"Deuflhard P, Hairer E, Zugck J: One-Step and Extrapolation Methods for Differential-Algebraic Systems. Numerische Mathematik. 1987, 51: 501-516. 10.1007\/BF01400352.","journal-title":"Numerische Mathematik"},{"key":"662_CR75","first-page":"1251","volume":"29","author":"T Prueksaritanont","year":"2001","unstructured":"Prueksaritanont T, Ma B, Fang X, Subramanian R, Yu J, Lin JH: beta-Oxidation of simvastatin in mouse liver preparations. Drug Metab Dispos. 2001, 29: 1251-1255.","journal-title":"Drug Metab Dispos"},{"key":"662_CR76","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1074\/mcp.M900020-MCP200","volume":"9","author":"WJ Deng","year":"2010","unstructured":"Deng WJ, Nie S, Dai J, Wu JR, Zeng R: Proteome, phosphoproteome, and hydroxyproteome of liver mitochondria in diabetic rats at early pathogenic stages. Mol Cell Proteomics. 2010, 9: 100-116. 10.1074\/mcp.M900020-MCP200","journal-title":"Mol Cell Proteomics"},{"key":"662_CR77","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1211\/jpp.61.10.0010","volume":"61","author":"TM Motawi","year":"2009","unstructured":"Motawi TM, Hashem RM, Rashed LA, El-Razek SM: Comparative study between the effect of the peroxisome proliferator activated receptor-alpha ligands fenofibrate and n-3 polyunsaturated fatty acids on activation of 5'-AMP-activated protein kinase-alpha1 in high-fat fed rats. J Pharm Pharmacol. 2009, 61: 1339-1346.","journal-title":"J Pharm Pharmacol"},{"key":"662_CR78","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","volume":"72","author":"MM Bradford","year":"1976","unstructured":"Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976, 72: 248-254. 10.1016\/0003-2697(76)90527-3","journal-title":"Anal Biochem"},{"key":"662_CR79","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1093\/ndt\/gfg048","volume":"18","author":"RL Lins","year":"2003","unstructured":"Lins RL, Matthys KE, Verpooten GA, Peeters PC, Dratwa M, Stolear JC, Lameire NH: Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients. Nephrol Dial Transplant. 2003, 18: 967-976. 10.1093\/ndt\/gfg048","journal-title":"Nephrol Dial Transplant"},{"key":"662_CR80","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.ijcard.2004.04.005","volume":"101","author":"V Launay-Vacher","year":"2005","unstructured":"Launay-Vacher V, Izzedine H, Deray G: Statins' dosage in patients with renal failure and cyclosporine drug-drug interactions in transplant recipient patients. Int J Cardiol. 2005, 101: 9-17. 10.1016\/j.ijcard.2004.04.005","journal-title":"Int J Cardiol"},{"key":"662_CR81","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/S0009-9236(98)90023-6","volume":"64","author":"T Kantola","year":"1998","unstructured":"Kantola T, Kivisto KT, Neuvonen PJ: Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther. 1998, 64: 58-65. 10.1016\/S0009-9236(98)90023-6","journal-title":"Clin Pharmacol Ther"},{"key":"662_CR82","doi-asserted-by":"publisher","first-page":"35669","DOI":"10.1074\/jbc.M103792200","volume":"276","author":"RG Tirona","year":"2001","unstructured":"Tirona RG, Leake BF, Merino G, Kim RB: Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem. 2001, 276: 35669-35675. 10.1074\/jbc.M103792200","journal-title":"J Biol Chem"},{"key":"662_CR83","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1124\/mol.60.5.934","volume":"60","author":"YH Cui","year":"2001","unstructured":"Cui YH, Konig J, Keppler D: Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2. Molecular Pharmacology. 2001, 60: 934-943.","journal-title":"Molecular Pharmacology"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-5-66.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T12:05:33Z","timestamp":1741176333000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-5-66"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,5,6]]},"references-count":83,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["662"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-5-66","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,5,6]]},"assertion":[{"value":"25 October 2010","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"66"}}