A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes

BMC Systems Biology

Volumn 5, Issue , 2011, Pages

  Bucher, Joachim ^a,g   Riedmaier, Stephan ^b   Schnabel, Anke ^c   Marcus, Katrin ^c   Vacun, Gabriele ^a,h   Weiss, Thomas S ^d   Thasler, Wolfgang E ^e   Nüssler, Andreas K ^f   Zanger, Ulrich M ^b   Reuss, Matthias ^a  

^a UNIVERSITY OF STUTTGART   (Germany)

^b UNIVERSITY OF TÜBINGEN   (Germany)

^c RUHR UNIVERSITY BOCHUM   (Germany)

^d UNIVERSITY OF REGENSBURG   (Germany)

^e LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^f TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^g INSILICO Biotechnology GmbH   (Germany)

^h FRAUNHOFER INSTITUTE FOR INTERFACIAL ENGINEERING AND BIOTECHNOLOGY IGB   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ATORVASTATIN; CYP3A4 PROTEIN, HUMAN; CYTOCHROME P450 3A; GLUCURONOSYLTRANSFERASE; HEPTANOIC ACID DERIVATIVE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LACTONE; PYRROLE DERIVATIVE; UDP GLUCURONOSYLTRANSFERASE, UGT1A3; UDP-GLUCURONOSYLTRANSFERASE, UGT1A3;

ARTICLE; BIOLOGICAL MODEL; DOSE RESPONSE; DRUG DETOXIFICATION; DRUG EFFECT; GENE EXPRESSION REGULATION; HUMAN; INTRACELLULAR SPACE; LIVER CELL; METABOLISM; METHODOLOGY; SYSTEMS BIOLOGY; TRANSPORT AT THE CELLULAR LEVEL;

BIOLOGICAL TRANSPORT; CYTOCHROME P-450 CYP3A; DOSE-RESPONSE RELATIONSHIP, DRUG; GENE EXPRESSION REGULATION, ENZYMOLOGIC; GLUCURONOSYLTRANSFERASE; HEPATOCYTES; HEPTANOIC ACIDS; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; INTRACELLULAR SPACE; LACTONES; METABOLIC DETOXICATION, PHASE I; METABOLIC DETOXICATION, PHASE II; MODELS, BIOLOGICAL; PYRROLES; SYSTEMS BIOLOGY;

EID: 79955662223     PISSN: None     EISSN: 17520509     Source Type: Journal    
DOI: 10.1186/1752-0509-5-66     Document Type: Article

References (83)

1. 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, 14960390.
2. van de Waterbeemd H, Gifford E. ADMET in silico modelling: Towards prediction paradise?. Nature Reviews Drug Discovery 2003, 2:192-204. 10.1038/nrd1032, 12612645.
3. 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, 17643090.
4. 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, 16935747.
5. Kitano H. Systems biology: a brief overview. Science 2002, 295:1662-1664. 10.1126/science.1069492, 11872829.
6. Spivey A. Systems biology - The big picture. Environmental Health Perspectives 2004, 112:A938-A943. 1247669, 15598608.
7. 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, 15205386.
8. 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, 11569527.
9. Lin JH. Sense and nonsense in the prediction of drug-drug interactions. Current Drug Metabolism 2000, 1:305-331. 10.2174/1389200003338947, 11465042.
10. 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, 11922953.
11. 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.
12. 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, 12904067.
13. 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, 9844807.
14. 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, 9508363.
15. 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, 17608404.
16. 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, 11922951.
17. 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, 11744617.
18. 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, 12523656.
19. 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, 17929911.
20. 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, 17381169.
21. 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.
22. 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, 21562827.
23. 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, 17268485.
24. 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, 7570672.
25. Gerlowski LE, Jain RK. Physiologically Based Pharmacokinetic Modeling - Principles and Applications. Journal of Pharmaceutical Sciences 1983, 72:1103-1127. 10.1002/jps.2600721003, 6358460.
26. Reddy M, Yang RS, Andersen ME, Clewell I, H J. Phyiologically Based Pharmacokinetic Modelling 2005, John Wiley & Sons.
27. 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.
28. Willmann S, Lippert J, Sevestre M, Solodenko J, Fois F, Schmitt W. PK-Sim®: a physiologically based pharmacokinetic 'whole-body' model. Biosilico 2003, 1.
29. 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, 16181128.
30. 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, 18991580.
31. Singh SS. Preclinical pharmacokinetics: An approach towards safer and efficacious drugs. Current Drug Metabolism 2006, 7:165-182. 10.2174/138920006775541552, 16472106.
32. Nestorov I. Whole-body physiologically based pharmacokinetic models. Expert Opinion on Drug Metabolism & Toxicology 2007, 3:235-249. 10.1517/17425255.3.2.235, 21548840.
33. Baker M, Parton T. Kinetic determinants of hepatic clearance: plasma protein binding and hepatic uptake. Xenobiotica 2007, 37:1110-1134. 10.1080/00498250701658296, 17968739.
34. 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, 18809732.
35. 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, 18426955.
36. 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, 15256870.
37. 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 2008, New York: Springer, Santin M.
38. 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.
39. 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.
40. 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, 19402041.
41. 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, 17470524.
42. 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, 11950779.
43. 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, 8272408.
44. 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, 19082953.
45. 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, 10931838.
46. 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, 15772423.
47. 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, 12644596.
48. 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, 15835926.
49. 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, 9804052.
50. 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.
51. 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, 15801541.
52. 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, 18720283.
53. 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, 21562798.
54. 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, 17192770.
55. 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, 16415531.
56. 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, 19940267.
57. 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, 17496207.
58. 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, 9632674.
59. 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, 17412826.
60. 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, 18411401.
61. 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, 1572659, 11250868.
62. 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, 10631627.
63. 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, 15616150.
64. 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.
65. 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, 16388406.
66. Chandra P, Brouwer KLR. The complexities of hepatic drug transport: Current knowledge and emerging concepts. Pharmaceutical Research 2004, 21:719-735.
67. 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, 9509899.
68. 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.
69. 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, 16882765.
70. 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, 17518592.
71. 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, 12485352.
72. 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, 17548463.
73. 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.
74. Deuflhard P, Hairer E, Zugck J. One-Step and Extrapolation Methods for Differential-Algebraic Systems. Numerische Mathematik 1987, 51:501-516.
75. 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.
76. 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, 2808256, 19700791.
77. 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.
78. 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, 942051.
79. 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, 12686673.
80. 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, 15860377.
81. 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, 9695720.
82. 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, 11477075.
83. 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.