Predicting Clearance Mechanism in Drug Discovery: Extended Clearance Classification System (ECCS)

Pharmaceutical Research

Volumn 32, Issue 12, 2015, Pages 3785-3802

  Varma, Manthena V ^a   Steyn, Stefanus J ^a   Allerton, Charlotte ^a   El Kattan, Ayman F ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

extended clearance classification system (ECCS); hepatic uptake; metabolism; permeability; renal clearance

Indexed keywords

AMPHOLYTE; DRUG;

ACTIVE TRANSPORT; ANIMAL CELL; APPARENT PERMEABILITY; BILIARY CLEARANCE; CLONAL CELL LINE; CONCEPTUAL FRAMEWORK; DRUG CLEARANCE; DRUG DEVELOPMENT; DRUG DISPOSITION; DRUG EXPOSURE; EXTENDED CLEARANCE CLASSIFICATION SYSTEM; GLOMERULUS FILTRATION RATE; HEPATIC CLEARANCE; HEPATIC EXTRACTION RATIO; HYDROPHOBICITY; INTRINSIC CLEARANCE; IONIZATION; LIPID SOLUBILITY; LIPOPHILICITY; LIVER BLOOD FLOW; MEMBRANE PERMEABILITY; MOLECULAR WEIGHT; NONHUMAN; PASSIVE TRANSPORT; PHARMACEUTICS; PHARMACOGENOMICS; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; RENAL CLEARANCE; REVIEW; ANIMAL; BIOLOGICAL MODEL; CELL LINE; CLASSIFICATION; DOG; HUMAN; KIDNEY; LIVER; METABOLIC CLEARANCE RATE; METABOLISM; PERMEABILITY; PROCEDURES; URINARY EXCRETION;

ANIMALS; CELL LINE; DOGS; DRUG DISCOVERY; HUMANS; KIDNEY; LIVER; METABOLIC CLEARANCE RATE; MODELS, BIOLOGICAL; PERMEABILITY; PHARMACEUTICAL PREPARATIONS; RENAL ELIMINATION;

EID: 84946478501     PISSN: 07248741     EISSN: 1573904X     Source Type: Journal    
DOI: 10.1007/s11095-015-1749-4     Document Type: Review

References (180)

1. Arrowsmith J. Trial watch: phase II failures: 2008-2010. Nat Rev Drug Discov. 2011;10:328-9.
2. Morgan P, Van Der Graaf PH, Arrowsmith J, Feltner DE, Drummond KS, Wegner CD, et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov Today. 2012;17:419-24.
3. Roffey SJ, Obach RS, Gedge JI, Smith DA. What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs. Drug Metab Rev. 2007;39:17-43.
4. Di L, Feng B, Goosen TC, Lai Y, Steyn SJ, Varma MV, et al. A perspective on the prediction of drug pharmacokinetics and disposition in drug research and development. Drug Metab Dispose Biol Fate Chem. 2013;41:1975-93.
5. Barton HA, Lai Y, Goosen TC, Jones HM, El-Kattan AF, Gosset JR, et al. Model-based approaches to predict drug-drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyond. Expert Opin Drug Metab Toxicol. 2013;9:459-72.
6. Elsby R, Hilgendorf C, Fenner K. Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1. Clin Pharmacol Ther. 2012;92:584-98.
7. Lai Y, Varma M, Feng B, Stephens JC, Kimoto E, El-Kattan A, et al. Impact of drug transporter pharmacogenomics on pharmacokinetic and pharmacodynamic variability - considerations for drug development. Expert Opin Drug Metab Toxicol. 2012;8:723-43.
8. Pang KS, Maeng HJ, Fan J. Interplay of transporters and enzymes in drug and metabolite processing. Mol Pharm. 2009;6:1734-55.
9. Shitara Y, Horie T, Sugiyama Y. Transporters as a determinant of drug clearance and tissue distribution. Eur J Pharm Sci. 2006;27:425-46.
10. Liu L, Pang KS. The roles of transporters and enzymes in hepatic drug processing. Drug Metab Dispose Biol Fate Chem. 2005;33:1-9.
11. Li R, Barton HA, Varma MV. Prediction of pharmacokinetics and drug-drug interactions when hepatic transporters are involved. Clin Pharmacokinet. 2014;53:659-78.
12. Maeda K, Ikeda Y, Fujita T, Yoshida K, Azuma Y, Haruyama Y, et al. Identification of the rate-determining process in the hepatic clearance of atorvastatin in a clinical cassette microdosing study. Clin Pharmacol Ther. 2011;90:575-81.
13. Pang KS, Rowland M. Hepatic clearance of drugs. I. Theoretical considerations of a "well-stirred" model and a "parallel tube" model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. J Pharmacokinet Biopharm. 1977;5:625-53.
14. Yoshida K, Maeda K, Sugiyama Y. Hepatic and intestinal drug transporters: prediction of pharmacokinetic effects caused by drug-drug interactions and genetic polymorphisms. Annu Rev Pharmacol Toxicol. 2013;53:581-612.
15. Yamazaki M, Suzuki H, Sugiyama Y. Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics. Pharm Res. 1996;13:497-513.
16. Sirianni GL, Pang KS. Organ clearance concepts: new perspectives on old principles. J Pharmacokinet Biopharm. 1997;25:449-70.
17. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther. 2006;112:71-105.
18. Camenisch G, Umehara K. Predicting human hepatic clearance from in vitro drug metabolism and transport data: a scientific and pharmaceutical perspective for assessing drug-drug interactions. Biopharm Drug Dispos. 2012;33:179-94.
19. Varma MV, Lin J, Bi YA, Rotter CJ, Fahmi OA, Lam JL, et al. Quantitative prediction of repaglinide-rifampicin complex drug interactions using dynamic and static mechanistic models: delineating differential CYP3A4 induction and OATP1B1 inhibition potential of rifampicin. Drug Metab Dispose Biol Fate Chem. 2013;41:966-74.
20. Camenisch G, Riede J, Kunze A, Huwyler J, Poller B, Umehara K. The extended clearance model and its use for the interpretation of hepatobiliary elimination data. ADMET DMPK. 2015;3:1-14.
21. De Buck SS, Sinha VK, Fenu LA, Nijsen MJ, Mackie CE, Gilissen RA. Prediction of human pharmacokinetics using physiologically based modeling: a retrospective analysis of 26 clinically tested drugs. Drug Metab Dispose Biol Fate Chem. 2007;35:1766-80.
22. Jones HM, Gardner IB, Collard WT, Stanley PJ, Oxley P, Hosea NA, et al. Simulation of human intravenous and oral pharmacokinetics of 21 diverse compounds using physiologically based pharmacokinetic modelling. Clin Pharmacokinet. 2011;50:331-47.
23. Obach RS, Baxter JG, Liston TE, Silber BM, Jones BC, Macintyre F, et al. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther. 1997;283:46-58.
24. Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004;32:1201-8.
25. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9:215-36.
26. Shugarts S, Bene LZ. The role of transporters in the pharmacokinetics of orally administered drugs. Pharm Res. 2009;26:2039-54.
27. Shitara Y, Maeda K, Ikejiri K, Yoshida K, Horie T, Sugiyama Y. Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos. 2013;34:45-78.
28. Fenner KS, Jones HM, Ullah M, Kempshall S, Dickins M, Lai Y, et al. The evolution of the OATP hepatic uptake transport protein family in DMPK sciences: from obscure liver transporters to key determinants of hepatobiliary clearance. Xenobiotica. 2012;42:28-45.
29. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158:693-705.
30. Shimizu K, Takashima T, Yamane T, Sasaki M, Kageyama H, Hashizume Y, et al. Whole-body distribution and radiation dosimetry of [11C]telmisartan as a biomarker for hepatic organic anion transporting polypeptide (OATP) 1B3. Nucl Med Biol. 2012;39:847-53.
31. Bergman E, Forsell P, Tevell A, Persson EM, Hedeland M, Bondesson U, et al. Biliary secretion of rosuvastatin and bile acids in humans during the absorption phase. Eur J Pharm Sci. 2006;29:205-14.
32. Yamazaki M, Kobayashi K, Sugiyama Y. Primary active transport of pravastatin across the liver canalicular membrane in normal and mutant Eisai hyperbilirubinemic rats. Biopharm Drug Dispos. 1996;17:607-21.
33. Varma MV, Lai Y, Feng B, Litchfield J, Goosen TC, Bergman A. Physiologically based modeling of pravastatin transporter-mediated hepatobiliary disposition and drug-drug interactions. Pharm Res. 2012.
34. Watanabe T, Kusuhara H, Maeda K, Shitara Y, Sugiyama Y. Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans. J Pharmacol Exp Ther. 2009;328:652-62.
35. Lau Y, Huang Y, Frassetto L, Benet L. Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2006;81:194-204.
36. Varma MV, Scialis RJ, Lin J, Bi YA, Rotter CJ, Goosen TC, et al. Mechanism-based pharmacokinetic modeling to evaluate transporter-enzyme interplay in drug interactions and pharmacogenetics of glyburide. AAPS J. 2014;16:736-48.
37. Zheng H, Huang Y, Frassetto L, Benet L. Elucidating rifampin's inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite. Clin Pharmacol Ther. 2008;85:78-85.
38. Kalliokoski A, Backman JT, Kurkinen KJ, Neuvonen PJ, Niemi M. Effects of gemfibrozil and atorvastatin on the pharmacokinetics of repaglinide in relation to SLCO1B1 polymorphism. Clin Pharmacol Ther. 2008;84:488-96.
39. Varma MV, Lai Y, Kimoto E, Goosen TC, El-Kattan AF, Kumar V. Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide. Pharm Res. 2013;30:1188-99.
40. Prueksaritanont T, Chu X, Evers R, Klopfer S, Caro L, Kothare P, Dempsey C, Rasmussen S, Houle R, Chan G. Pitavastatin is a more sensitive and selective OATP1B clinical probe than rosuvastatin. Br J Clin Pharmacol. 2014.
41. Group SC, Link E, Parish S, Armitage J, Bowman L, Heath S, et al. SLCO1B1 variants and statin-induced myopathy - a genomewide study. N Engl J Med. 2008;359:789-99.
42. Ieiri I, Higuchi S, Sugiyama Y. Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Exp Opin Drug Metab Toxicol. 2009;5:703-29.
43. Niemi M, Neuvonen PJ, Hofmann U, Backman JT, Schwab M, Lutjohann D, et al. Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype∗17. Pharmacogenet Genomics. 2005;15:303-9.
44. Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T, et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther. 2003;73:554-65.
45. Varma MV, Chang G, Lai Y, Feng B, El-Kattan AF, Litchfield J, et al. Physicochemical property space of hepatobiliary transport and computational models for predicting rat biliary excretion. Drug Metab Dis Biol Fate Chem. 2012;40:1527-37.
46. Kusuhara H, Sugiyama Y. Pharmacokinetic modeling of the hepatobiliary transport mediated by cooperation of uptake and efflux transporters. Drug Metab Rev. 2010;42:539-50.
47. Lai Y. Identification of interspecies difference in hepatobiliary transporters to improve extrapolation of human biliary secretion. Exp Opin Drug Metab Toxicol. 2009;5:1175-87.
48. Yamashiro W, Maeda K, Hirouchi M, Adachi Y, Hu Z, Sugiyama Y. Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug Metab Dis Biol Fate Chem. 2006;34:1247-54.
49. Poirier A, Cascais A-C, Funk C, Lavé T. Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data. J Pharmacokinet Pharmacodyn. 2009;36:585-611.
50. Yang X, Gandhi YA, Duignan DB, Morris ME. Prediction of biliary excretion in rats and humans using molecular weight and quantitative structure-pharmacokinetic relationships. AAPS J. 2009;11:511-25.
51. Fagerholm U. Prediction of human pharmacokinetics-biliary and intestinal clearance and enterohepatic circulation. J Pharm Pharmacol. 2008;60:535-42.
52. Luo G, Johnson S, Hsueh MM, Zheng J, Cai H, Xin B, et al. In silico prediction of biliary excretion of drugs in rats based on physicochemical properties. Drug Metab Dis Biol Fate Chem. 2010;38:422-30.
53. Millburn P, Smith RL, Williams RT. Biliary excretion in foreign compounds. Sulphonamide drugs in the rat. Biochem J. 1967;105:1283-7.
54. Millburn P, Smith RL, Williams RT. Biliary excretion of foreign compounds. Biphenyl, stilboestrol and phenolphthalein in the rat: molecular weight, polarity and metabolism as factors in biliary excretion. Biochem J. 1967;105:1275-81.
55. Kato Y, Takahara S, Kato S, Kubo Y, Sai Y, Tamai I, et al. Involvement of multidrug resistance-associated protein 2 (Abcc2) in molecular weight-dependent biliary excretion of beta-lactam antibiotics. Drug Metab Dis Biol Fate Chem. 2008;36:1088-96.
56. Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 2009;323:1718-22.
57. Gandhi YA, Morris ME. Structure-activity relationships and quantitative structure-activity relationships for breast cancer resistance protein (ABCG2). AAPS J. 2009;11:541-52.
58. Matsson P, Pedersen JM, Norinder U, Bergstrom CA, Artursson P. Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs. Pharm Res. 2009;26:1816-31.
59. Varma MV, Ambler CM, Ullah M, Rotter CJ, Sun H, Litchfield J, et al. Targeting intestinal transporters for optimizing oral drug absorption. Curr Drug Metab. 2010;11:730-42.
60. Varma MV, Panchagnula R. pH-dependent functional activity of P-glycoprotein in limiting intestinal absorption of protic drugs: kinetic analysis of quinidine efflux in situ. J Pharm Sci. 2005;94:2632-43.
61. Varma MV, Gardner I, Steyn SJ, Nkansah P, Rotter CJ, Whitney-Pickett C, et al. pH-Dependent solubility and permeability criteria for provisional biopharmaceutics classification (BCS and BDDCS) in early drug discovery. Mol Pharm. 2012;9:1199-212.
62. Song IS, Choi MK, Jin QR, Shim WS, Shim CK. Increased affinity to canalicular P-gp via formation of lipophilic ion-pair complexes with endogenous bile salts is associated with mw threshold in hepatobiliary excretion of quaternary ammonium compounds. Pharm Res. 2010;27:823-31.
63. Benet LZ, Broccatelli F, Oprea TI. BDDCS applied to over 900 drugs. AAPS J. 2011;13:519-47.
64. Custodio JM, Wu C-Y, Benet LZ. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Adv Drug Deliv Rev. 2008;60:717-33.
65. Wu C-Y, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22:11-23.
66. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2012;64:4-17.
67. Veber DF, Johnson SR, Cheng H-Y, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45:2615-23.
68. Camenisch G, Alsenz J, van de Waterbeemd H, Folkers G. Estimation of permeability by passive diffusion through Caco-2 cell monolayers using the drugs' lipophilicity and molecular weight. Eur J Pharm Sci. 1998;6:313-9.
69. Varma MV, Obach RS, Rotter C, Miller HR, Chang G, Steyn SJ, et al. Physicochemical space for optimum oral bioavailability: contribution of human intestinal absorption and first-pass elimination. J Med Chem. 2010;53:1098-108.
70. Obach RS, Lombardo F, Waters NJ. Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds. Drug Metab Dis Biol Fate Chem. 2008;36:1385-405.
71. Lewis DF. Homology modelling of human cytochromes P450 involved in xenobiotic metabolism and rationalization of substrate selectivity. Exp Toxicol Pathol. 1999;51:369-74.
72. Lewis DF, Modi S, Dickins M. Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev. 2002;34:69-82.
73. Ho RH, Kim RB. Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther. 2005;78:260-77.
74. Shitara Y, Sato H, Sugiyama Y. Evaluation of drug-drug interaction in the hepatobiliary and renal transport of drugs. 2005;45:689-723.
75. Fagerholm U. Prediction of human pharmacokinetics - renal metabolic and excretion clearance. J Pharm Pharmacol. 2007;59:1463-71.
76. Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther. 2006;109:1-11.
77. Jappar D, Hu Y, Keep RF, Smith DE. Transport mechanisms of carnosine in SKPT cells: contribution of apical and basolateral membrane transporters. Pharm Res. 2009;26:172-81.
78. Masereeuw R, Russel FG. Mechanisms and clinical implications of renal drug excretion. Drug Metab Rev. 2001;33:299-351.
79. Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, et al. Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1. J Med Chem. 2008;51:5932-42.
80. Inui KI, Masuda S, Saito H. Cellular and molecular aspects of drug transport in the kidney. Kidney Int. 2000;58:944-58.
81. Launay-Vacher V, Izzedine H, Karie S, Hulot JS, Baumelou A, Deray G. Renal tubular drug transporters. Nephron Physiol. 2006;103:p97-106.
82. Varma MV, Feng B, Obach RS, Troutman MD, Chupka J, Miller HR, et al. Physicochemical determinants of human renal clearance. J Med Chem. 2009;52:4844-52.
83. Goodwin JT, Conradi RA, Ho NF, Burton PS. Physicochemical determinants of passive membrane permeability: role of solute hydrogen-bonding potential and volume. J Med Chem. 2001;44:3721-9.
84. Varma MV, Sateesh K, Panchagnula R. Functional role of P-glycoprotein in limiting intestinal absorption of drugs: contribution of passive permeability to P-glycoprotein mediated efflux transport. Mol Pharm. 2005;2:12-21.
85. Ullrich KJ. Renal transporters for organic anions and organic cations. Structural requirements for substrates. J Membr Biol. 1997;158:95-107.
86. Bednarczyk D, Ekins S, Wikel JH, Wright SH. Influence of molecular structure on substrate binding to the human organic cation transporter, hOCT1. Mol Pharmacol. 2003;63:489-98.
87. Feng B, LaPerle JL, Chang G, Varma MV. Renal clearance in drug discovery and development: molecular descriptors, drug transporters and disease state. Exp Opin Drug Metab Toxicol. 2010;6:939-52.
88. Berellini G, Waters NJ, Lombardo F. In silico prediction of total human plasma clearance. J Chem Inf Model. 2012;52:2069-78.
89. Lombardo F, Obach RA, Varma MV, Stringer R, Berellini G. Clearance mechanism assignment and total clearance prediction in human based upon in silico models. J Med Chem. 2014.
90. Kusama M, Toshimoto K, Maeda K, Hirai Y, Imai S, Chiba K, et al. In silico classification of major clearance pathways of drugs with their physiochemical parameters. Drug Metab Dispos. 2010;38:1362-70.
91. Varma MV, Bi YA, Kimoto E, Lin J. Quantitative prediction of transporter- and enzyme-mediated clinical drug-drug interactions of organic anion-transporting polypeptide 1B1 substrates using a mechanistic net-effect model. J Pharmacol Exp Ther. 2014;351:214-23.
92. Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63:157-81.
93. Gupta RR, Gifford EM, Liston T, Waller CL, Hohman M, Bunin BA, et al. Using open source computational tools for predicting human metabolic stability and additional absorption, distribution, metabolism, excretion, and toxicity properties. Drug Metab Dispos. 2010;38:2083-90.
94. Tang M, Mukundan M, Yang J, Charpentier N, LeCluyse EL, Black C, et al. Antiplatelet agents aspirin and clopidogrel are hydrolyzed by distinct carboxylesterases, and clopidogrel is transesterificated in the presence of ethyl alcohol. J Pharmacol Exp Ther. 2006;319:1467-76.
95. Davies NM, Anderson KE. Clinical pharmacokinetics of diclofenac. Therapeutic insights and pitfalls. Clin Pharmacokinet. 1997;33:184-213.
96. King C, Tang W, Ngui J, Tephly T, Braun M. Characterization of rat and human UDP-glucuronosyltransferases responsible for the in vitro glucuronidation of diclofenac. Toxicol Sci Off J Soc Toxicol. 2001;61:49-53.
97. 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 Metab Dis Biol Fate Chem. 2004;32:715-21.
98. McGinnity DF, Parker AJ, Soars M, Riley RJ. Automated definition of the enzymology of drug oxidation by the major human drug metabolizing cytochrome P450s. Drug Metab Dis Biol Fate Chem. 2000;28:1327-34.
99. Kirchheiner J, Thomas S, Bauer S, Tomalik-Scharte D, Hering U, Doroshyenko O, et al. Pharmacokinetics and pharmacodynamics of rosiglitazone in relation to CYP2C8 genotype. Clin Pharmacol Ther. 2006;80:657-67.
100. Chu XM, Zhang LF, Wang GJ, Zhang SN, Zhou JH, Hao HP. Influence of UDP-glucuronosyltransferase polymorphisms on valproic acid pharmacokinetics in Chinese epilepsy patients. Eur J Clin Pharmacol. 2012;68:1395-401.
101. Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet. 2001;40:587-603.
102. Lennernas H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42:1141-60.
103. Lau YY, Okochi H, Huang Y, Benet LZ. Multiple transporters affect the disposition of atorvastatin and its two active hydroxy metabolites: application of in vitro and ex situ systems. J Pharmacol Exp Ther. 2006;316:762-71.
104. Dingemanse J, van Giersbergen PL. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43:1089-115.
105. Shitara Y, Hirano M, Sato H, Sugiyama Y. Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J Pharmacol Exp Ther. 2004;311:228-36.
106. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565-81.
107. Hirano M, Maeda K, Shitara Y, Sugiyama Y. Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther. 2004;311:139-46.
108. Fujino H, Saito T, Tsunenari Y, Kojima J. Effect of gemfibrozil on the metabolism of pitavastatin - determining the best animal model for human CYP and UGT activities. Drug Metabol Drug Interact. 2004;20:25-42.
109. Li R, Ghosh A, Maurer TS, Kimoto E, Barton HA. Physiologically based pharmacokinetic prediction of telmisartan in human. Drug Metab Dis Biol Fate Chem. 2014;42:1646-55.
110. McDowell JA, Chittick GE, Stevens CP, Edwards KD, Stein DS. Pharmacokinetic interaction of abacavir (1592U89) and ethanol in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2000;44:1686-90.
111. Pea F, Furlanut M. Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions. Clin Pharmacokinet. 2001;40:833-68.
112. Baneyx G, Parrott N, Meille C, Iliadis A, Lave T. Physiologically based pharmacokinetic modeling of CYP3A4 induction by rifampicin in human: influence of time between substrate and inducer administration. Eur J Pharm Sci. 2014;56:1-15.
113. Samer CF, Lorenzini KI, Rollason V, Daali Y, Desmeules JA. Applications of CYP450 testing in the clinical setting. Mol Diagn Ther. 2013;17:165-84.
114. Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs Drugs Devices Interv. 2004;4:281-97.
115. Edsbacker S, Andersson T. Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease. Clin Pharmacokinet. 2004;43:803-21.
116. Brosen K. Drug interactions and the cytochrome P450 system. The role of cytochrome P450 1A2. Clin Pharmacokinet. 1995;29(1):20-5.
117. Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A. Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs. Biol Pharm Bull. 2005;28:1711-6.
118. Sutton D, Butler AM, Nadin L, Murray M. Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. J Pharm Exp Ther. 1997;282:294-300.
119. van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009;35:692-706.
120. Ohno Y, Hisaka A, Suzuki H. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs. Clin Pharmacokinet. 2007;46:681-96.
121. Bogni A, Monshouwer M, Moscone A, Hidestrand M, Ingelman-Sundberg M, Hartung T, et al. Substrate specific metabolism by polymorphic cytochrome P450 2D6 alleles. Toxicol In Vitro Int J Publ Assoc BIBRA. 2005;19:621-9.
122. Jeong H, Choi S, Song JW, Chen H, Fischer JH. Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica. 2008;38:62-75.
123. Paine MF, Shen DD, Kunze KL, Perkins JD, Marsh CL, McVicar JP, et al. First-pass metabolism of midazolam by the human intestine. Clin Pharmacol Ther. 1996;60:14-24.
124. Crowe A. The influence of P-glycoprotein on morphine transport in Caco-2 cells. Comparison with paclitaxel. Eur J Pharmacol. 2002;440:7-16.
125. Chau N, Elliot DJ, Lewis BC, Burns K, Johnston MR, Mackenzie PI, et al. Morphine glucuronidation and glucosidation represent complementary metabolic pathways that are both catalyzed by UDP-glucuronosyltransferase 2B7: kinetic, inhibition, and molecular modeling studies. J Pharmacol Exp Ther. 2014;349:126-37.
126. Foti RS, Rock DA, Wienkers LC, Wahlstrom JL. Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dis Biol Fate Chem. 2010;38:981-7.
127. Kanazawa H, Okada A, Higaki M, Yokota H, Mashige F, Nakahara K. Stereospecific analysis of omeprazole in human plasma as a probe for CYP2C19 phenotype. J Pharm Biomed Anal. 2003;30:1817-24.
128. Narimatsu S, Nakata T, Shimizudani T, Nagaoka K, Nakura H, Masuda K, et al. Regio- and stereoselective oxidation of propranolol enantiomers by human CYP2D6, cynomolgus monkey CYP2D17 and marmoset CYP2D19. Chem Biol Interact. 2011;189:146-52.
129. Gupta M, Kovar A, Meibohm B. The clinical pharmacokinetics of phosphodiesterase-5 inhibitors for erectile dysfunction. J Clin Pharmacol. 2005;45:987-1003.
130. Leveque D, Nivoix Y, Jehl F, Herbrecht R. Clinical pharmacokinetics of voriconazole. Int J Antimicrob Agents. 2006;27:274-84.
131. Jeu L, Piacenti FJ, Lyakhovetskiy AG, Fung HB. Voriconazole. Clin Ther. 2003;25:1321-81.
132. Beedham C, Miceli JJ, Obach RS. Ziprasidone metabolism, aldehyde oxidase, and clinical implications. J Clin Psychopharmacol. 2003;23:229-32.
133. Li M, Anderson GD, Phillips BR, Kong W, Shen DD, Wang J. Interactions of amoxicillin and cefaclor with human renal organic anion and peptide transporters. Drug Metab Dis Biol Fate Chem. 2006;34:547-55.
134. Ueo H, Motohashi H, Katsura T, Inui K. Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1. Biochem Pharmacol. 2005;70:1104-13.
135. Hasannejad H, Takeda M, Taki K, Shin HJ, Babu E, Jutabha P, et al. Interactions of human organic anion transporters with diuretics. J Pharm Exp Ther. 2004;308:1021-9.
136. Ye J, Liu Q, Wang C, Meng Q, Sun H, Peng J, et al. Benzylpenicillin inhibits the renal excretion of acyclovir by OAT1 and OAT3. Pharmacol Rep PR. 2013;65:505-12.
137. Liu Q, Wang C, Meng Q, Huo X, Sun H, Peng J, et al. MDR1 and OAT1/OAT3 mediate the drug-drug interaction between puerarin and methotrexate. Pharm Res. 2014;31:1120-32.
138. El-Sheikh AA, Greupink R, Wortelboer HM, van den Heuvel JJ, Schreurs M, Koenderink JB, et al. Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4. Transl Re J Lab Clin Med. 2013;162:398-409.
139. Kitamura S, Maeda K, Wang Y, Sugiyama Y. Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dis Biol Fate Chem. 2008;36:2014-23.
140. Ye J, Liu Q, Wang C, Meng Q, Peng J, Sun H, et al. Inhibitory effect of JBP485 on renal excretion of acyclovir by the inhibition of OAT1 and OAT3. Eur J Pharm Sci. 2012;47:341-6.
141. Tahara H, Kusuhara H, Endou H, Koepsell H, Imaoka T, Fuse E, et al. A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters. J Pharmacol Exp Ther. 2005;315:337-45.
142. Muller F, Konig J, Hoier E, Mandery K, Fromm MF. Role of organic cation transporter OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2-K for transport and drug interactions of the antiviral lamivudine. Biochem Pharmacol. 2013;86:808-15.
143. Choi CI, Bae JW, Keum SK, Lee YJ, Lee HI, Jang CG, et al. Effects of OCT2 c.602C > T genetic variant on the pharmacokinetics of lamivudine. Xenobiotica. 2013;43:636-40.
144. Bourdet DL, Pritchard JB, Thakker DR. Differential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). J Pharmacol Exp Ther. 2005;315:1288-97.
145. Chu XY, Bleasby K, Yabut J, Cai X, Chan GH, Hafey MJ, et al. Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J Pharmacol Exp Ther. 2007;321:673-83.
146. Lewis DF. Modelling human cytochromes P450 for evaluating drug metabolism: an update. Drug Metabol Drug Interact. 2000;16:307-24.
147. Hosea NA, Collard WT, Cole S, Maurer TS, Fang RX, Jones H, et al. Prediction of human pharmacokinetics from preclinical information: comparative accuracy of quantitative prediction approaches. J Clin Pharmacol. 2009;49:513-33.
148. He YJ, Zhang W, Chen Y, Guo D, Tu JH, Xu LY, et al. Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism. Clin Chim Acta Int J Clin Chem. 2009;405:49-52.
149. Asberg A, Hartmann A, Fjeldsa E, Bergan S, Holdaas H. Bilateral pharmacokinetic interaction between cyclosporine A and atorvastatin in renal transplant recipients. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2001;1:382-6.
150. Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P. Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin. Clin Pharmacol Ther. 2000;68:391-400.
151. Amsden GW, Kuye O, Wei GC. A study of the interaction potential of azithromycin and clarithromycin with atorvastatin in healthy volunteers. J Clin Pharmacol. 2002;42:444-9.
152. Siedlik PH, Olson SC, Yang BB, Stern RH. Erythromycin coadministration increases plasma atorvastatin concentrations. J Clin Pharmacol. 1999;39:501-4.
153. Prueksaritanont T, Chu X, Evers R, Klopfer SO, Caro L, Kothare PA, et al. Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin. Br J Clin Pharmacol. 2014;78:587-98.
154. Muck W, Mai I, Fritsche L, Ochmann K, Rohde G, Unger S, et al. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther. 1999;65:251-61.
155. Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther. 2002;72:685-91.
156. Kantola T, Backman JT, Niemi M, Kivisto KT, Neuvonen PJ. Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol. 2000;56:225-9.
157. Park JW, Siekmeier R, Lattke P, Merz M, Mix C, Schuler S, et al. Pharmacokinetics and pharmacodynamics of fluvastatin in heart transplant recipients taking cyclosporine A. J Cardiovasc Pharmacol Ther. 2001;6:351-61.
158. Transon C, Leemann T, Vogt N, Dayer P. in vivo inhibition profile of cytochrome P450TB (CYP2C9) by (+/-)-fluvastatin. Clin Pharmacol Ther. 1995;58:412-7.
159. Muck W, Ochmann K, Rohde G, Unger S, Kuhlmann J. Influence of erythromycin pre- and co-treatment on single-dose pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin. Eur J Clin Pharmacol. 1998;53:469-73.
160. Li R, Barton HA, Yates PD, Ghosh A, Wolford AC, Riccardi KA, Maurer TS. A "middle-out" approach to human pharmacokinetic predictions for OATP substrates using physiologically-based pharmacokinetic modeling. J Pharmacokinet Pharmacodyn. 2014.
161. Jones HM, Barton HA, Lai Y, Bi YA, Kimoto E, Kempshall S, et al. Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data. Drug Metab Dis Biol Fate Chem. 2012;40:1007-17.
162. Soars MG, Grime K, Sproston JL, Webborn PJ, Riley RJ. Use of hepatocytes to assess the contribution of hepatic uptake to clearance in vivo. Drug Metab Dispos. 2007;35:859-65.
163. Ménochet K, Kenworthy KE, Houston JB, Galetin A. Use of mechanistic modeling to assess interindividual variability and interspecies differences in active uptake in human and rat hepatocytes. Drug Metab Dispos. 2012;40:1744-56.
164. Swift B, Pfeifer ND, Brouwer KL. Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity. Drug Metab Rev. 2010;42:446-71.
165. Watanabe T, Kusuhara H, Maeda K, Kanamaru H, Saito Y, Hu Z, et al. Investigation of the rate-determining process in the hepatic elimination of HMG-CoA reductase inhibitors in rats and humans. Drug Metab Dispos. 2010;38:215-22.
166. Greenblatt DJ, Peters DE, Oleson LE, Harmatz JS, MacNab MW, Berkowitz N, et al. Inhibition of oral midazolam clearance by boosting doses of ritonavir, and by 4,4-dimethyl-benziso-(2H)-selenazine (ALT-2074), an experimental catalytic mimic of glutathione oxidase. Br J Clin Pharmacol. 2009;68:920-7.
167. Tomita Y, Maeda K, Sugiyama Y. Ethnic variability in the plasma exposures of OATP1B1 substrates such as HMG-CoA reductase inhibitors: a kinetic consideration of its mechanism. Clin Pharmacol Ther. 2013;94:37-51.
168. Maeda K, Sugiyama Y. Transporter biology in drug approval: regulatory aspects. Mol Asp Med. 2013;34:711-8.
169. Paine SW, Ménochet K, Denton R, McGinnity DF, Riley RJ. Prediction of human renal clearance from preclinical species for a diverse set of drugs that exhibit both active secretion and net reabsorption. Drug Metab Dispos. 2011;39:1008-13.
170. Feng B, Varma MV, Costales C, Zhang H, Tremaine L. In vitro and in vivo approaches to characterize transporter-mediated disposition in drug discovery. Exp Opin Drug Disc. 2014;9:873-90.
171. Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12:413-20.
172. CDER/FDA. Guidance for industry: Waiver of in vivo bioavailability and bioequivalence studies for imidiate-release solid oral dosage forms based on a biopharmaceutics classification system. Center for Drug Evaluation and Research 2000.
173. Varma MV, Khandavilli S, Ashokraj Y, Jain A, Dhanikula A, Sood A, et al. Biopharmaceutic classification system: a scientific framework for pharmacokinetic optimization in drug research. Curr Drug Metab. 2004;5:375-88.
174. Lennernas H. Human intestinal permeability. J Pharm Sci. 1998;87:403-10.
175. Sandstrom R, Karlsson A, Knutson L, Lennernas H. Jejunal absorption and metabolism of R/S-verapamil in humans. Pharm Res. 1998;15:856-62.
176. Benet LZ, Amidon GL, Barends DM, Lennernas H, Polli JE, Shah VP, et al. The use of BDDCS in classifying the permeability of marketed drugs. Pharm Res. 2008;25:483-8.
177. Chen ML, Amidon GL, Benet LZ, Lennernas H, Yu LX, The BCS. BDDCS, and regulatory guidances. Pharm Res. 2011;28:1774-8.
178. Avdeef A. Absorption and drug development: solubility, permeability, and charge state. John Wiley & Sons, 2012.
179. Lee PH, Ayyampalayam SN, Carreira LA, Shalaeva M, Bhattachar S, Coselmon R, et al. In silico prediction of ionization constants of drugs. Mol Pharm. 2007;4:498-512.
180. Fan PW, Song Y, Berezhkovskiy LM, Cheong J, Plise EG, Khojasteh SC. Practical permeability-based hepatic clearance classification system (HepCCS) in drug discovery. Future Med Chem. 2014;6:1995-2012.