In vitro-in vivo extrapolation of hepatic clearance: Biological tools, scaling factors, model assumptions and correct concentrations

Xenobiotica

Volumn 37, Issue 10-11, 2007, Pages 1066-1089

  Pelkonen, O ^a   Turpeinen, M ^a,b  

^a UNIVERSITY OF OULU   (Finland)

^b Novamass Analytical Ltd   (Finland)

Author keywords

Extrapolation of in vitro data; Hepatic clearance extrapolation; Hepatocytes; Homogenates; Human liver; In vitro incubation; Microsomes; Recombinant enzymes; Scaling factors; Slices

Indexed keywords

RECOMBINANT ENZYME;

BLOOD FLOW; CELL LINE; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DISTRIBUTION; HUMAN; IN VITRO SELECTION; IN VIVO STUDY; LIVER CELL; LIVER CLEARANCE; LIVER SLICE; LIVER WEIGHT; MICROSOME; REVIEW;

BIOLOGICAL TRANSPORT, ACTIVE; BIOTRANSFORMATION; CELLS, CULTURED; ENZYMES; HUMANS; LIVER; LIVER CIRCULATION; METABOLIC CLEARANCE RATE; MODELS, BIOLOGICAL; RECOMBINANT PROTEINS; SUBCELLULAR FRACTIONS; XENOBIOTICS;

EID: 35648944767     PISSN: 00498254     EISSN: 13665928     Source Type: Journal    
DOI: 10.1080/00498250701620726     Document Type: Review

References (109)

1. Allen DD, Caviedes R, Cardenas AM, Shimahara T, Segura-Aguilar J, Caviedes PA. 2005. Cell lines as in vitro models for drug screening and toxicity studies. Drug Development and Industrial Pharmacology 31:757-768.
2. Aninat C, Piton A, Glaise D, Le Charpentier T, Langouet S, Morel F, Guguen-Guillouzo C, Guillouzo A. 2006. Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metabolism and Disposition 34:75-83.
3. Arias I. 1988. The Liver: Biology and Pathobiology, Ed., 2. In: Arias I, Jakoby W, Popper H, Schachter D, Shafritz D, editors. Introduction. New York, NY: Raven. pp 3-10.
4. Austin RP, Barton P, Cockroft SL, Wenlock MC, Riley RJ. 2002. The influence of nonspecific microsomal binding on apparent intrinsic clearance, and its prediction from physicochemical properties. Drug Metabolism and Disposition 30:1497-1503.
5. Austin RP, Barton P, Mohmed S, Riley RJ. 2005. The binding of drugs to hepatocytes and its relationship to physicochemical properties. Drug Metabolism and Disposition 33:419-425.
6. Barter ZE, Bayliss MK, Beaune PH, Boobis AR, Carlile DJ, Edwards RJ, Houston JB, Lake BG, Lipscomb JC, Pelkonen OR, et al. 2007. Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver. Current Drug Metabolism 8:33-45.
7. Bayliss MK, Bell JA, Jenner WN, Wilson K. 1990. Prediction of intrinsic clearance of loxtidine from kinetic studies in rat, dog and human hepatocytes. Biochemistry Society Transactions 18:1198-1199.
8. Bernauer U, Glatt H, Heinrich-Hirsch B, Liu Y, Muckel E, Vieth B, Gundert-Remy U. 2003. Heterologous expression of mouse cytochrome P450 2e1 in V79 cells: Construction and characterisation of the cell line and comparison with V79 cell lines stably expressing rat P450 2E1 and human P450 2E1. Alternate Laboratory Animals 31:21-30.
9. Bernauer U, Heinrich-Hirsch B, Tönnies M, Wolski PM, Gundert-Remy U. 2006. Characterisation of the xenobiotic-metabolizing cytochrome P450 expression pattern in human lung tissue by immunochemical and activity determination. Toxicology Letters 164:278-288.
10. Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, et al. 2003. The conduct of in vitro and in vivo drug-drug interaction studies: A PhRMA perspective. Journal of Clinical Pharmacology 43:443-469.
11. Boobis AR, McKillop D, Robinson DT, Adams DA, McCormick DJ. 1998. Interlaboratory comparison of the assessment of P450 activities in human hepatic microsomal samples. Xenobiotica 28:493-506.
12. Chandra P, Brouwer KL. 2004. The complexities of hepatic drug transport: Current knowledge and emerging concepts. Pharmacology Research 21:719-735.
13. Chaturvedi PR, Decker CJ, Odinecs A. 2001. Prediction of pharmacokinetic properties using experimental approaches during early drug discovery. Current Opinions in Chemistry and Biology 5:452-563.
14. Coecke S, Ahr H, Blaauboer BJ, Bremer S, Casati S, Castell J, Combes R, Corvi R, Crespi CL, Cunningham ML, et al. 2006. Metabolism: A bottleneck in in vitro toxicological test development. The Report and Recommendations of ECVAM Workshop 54. Alternate Laboratory Animals 34:49-84.
15. Crespi CL, Miller VP. 1999. The use of heterologously expressed drug metabolizing enzymes - state of the art and prospects for the future. Pharmacology and Therapy 84:121-131.
16. Cross DM, Bayliss MK. 2000. A commentary on the use of hepatocytes in drug metabolism studies during drug discovery and development. Drug Metabolism Reviews 32:219-240.
17. Edwards RJ, Price RJ, Watts PS, Renwick AB, Tredger JM, Boobis AR, Lake BG. 2003. Induction of cytochrome P450 enzymes in cultured precision-cut human liver slices. Drug Metabolism and Disposition 31:282-288.
18. Ekins S, Mäenpää J, Wrighton SA. 1999. In vitro metabolism: subcellular fractions. In: Woolf TF, editor. Handbook of drug metabolism. New York, NY: Marcel Dekker. pp 363-399.
19. Ekins S, Ring BJ, Grace J, McRobie-Belle DJ, Wrighton SA. 2000. Present and future in vitro approaches for drug metabolism. Journal of Pharmacology and Toxicology Methods 44:313-324.
20. Ekins S, Williams JA, Murray GI, Burke MD, Marchant NC, Engeset J, Hawksworth GM. 1996. Xenobiotic metabolism in rat, dog, and human precision-cut liver slices, freshly isolated hepatocytes, and vitrified precisioncut liver slices. Drug Metabolism and Disposition 24:990-995.
21. Ferrero JL, Brendel K. 1997. Liver slices as a model in drug metabolism. Advances in Pharmacology 43:131-169.
22. Friedberg T, Henderson CJ, Pritchard MP, Wolf CR. 1999. In vivo and in vitro recombinant DNA technology as a powerful tool in drug development. In: Woolf TF, editor. Handbook of drug metabolism. New York, NY: Marcel Dekker. pp 322-362.
23. Ghibellini G, Vasist LS, Leslie EM, Heizer WD, Kowalsky RJ, Calvo BF, Brouwer KL. 2007. In vitro-in vivo correlation of hepatobiliary drug clearance in humans. Clinical Pharmacology and Therapy 81:406-413.
24. Glöckner R, Steinmetzer P, Drobner C, Muller D. 1998. Application of cryopreserved precision-cut liver slices in pharmacotoxicology - principles, literature data and own investigations with special reference to CYP1A1-mRNA induction. Experiments in Toxicology and Pathology 50:440-449.
25. Gomez-Lechon MJ, Donato T, Ponsoda X, Castell JV. 2003. Human hepatic cell cultures: In vitro and in vivo drug metabolism. Alternate Laboratory Animals 31:257-265.
26. Gomez-Lechon MJ, Donato MT, Castell JV, Jover R. 2004. Human hepatocytes in primary culture: The choice to investigate drug metabolism in man. Current Drug Metabolism 5:443-462.
27. Gomez-Lechon MJ, Donato T, Jover R, Rodriguez C, Ponsoda X, Glaise D, Castell JV, Guguen-Guillouzo C. 2001. Expression and induction of a large set of drug-metabolizing enzymes by the highly differentiated human hepatoma cell line BC2. European Journal of Biochemistry 268:1448-1459.
28. Grime K, Riley RJ. 2006. The impact of in vitro binding on in vitro-in vivo extrapolations, projections of metabolic clearance and clinical drug-drug interactions. Current Drug Metabolism 7:251-264.
29. Gripon P, Rumin S, Urban S, Le Seyec J, Glaise D, Cannie I, Guyomard C, Lucas J, Trepo C, Guguen-Guillouzo C. (2002). Infection of a human hepatoma cell line by hepatitis B virus. Proceedings of the National Academy of Sciences, USA 99: 15655-15660.
30. Guillouzo A. 1995. Acquisition and use of human in vitro liver preparations. Cell Biology and Toxicology 11:141-145.
31. Guillouzo A, Corlu A, Aninat C, Glaise D, Morel F, Guguen-Guillouzo C. 2007. The human hepatoma HepaRG cells: A highly differentiated model for studies of liver metabolism and toxicity of xenobiotics. Chemico-Biological Interactions 168:66-73.
32. Hakooz N, Ito K, Rawden H, Gill H, Lemmers L, Boobis AR, Edwards RJ, Carlile DJ, Lake BG, Houston JB. 2006. Determination of a human hepatic microsomal scaling factor for predicting in vivo drug clearance. Pharmacology Research 23:533-539.
33. Heinemann A, Wischhusen F, Puschel K, Rogiers X. 1999. Standard liver volume in the Caucasian population. Liver Transplant Surgery 5:366-368.
34. Hengstler JG, Utesch D, Steinberg P, Platt KL, Diener B, Ringel M, Swales N, Fischer T, Biefang K, Gerl M, et al. 2000. Cryopreserved primary hepatocytes as a constantly available in vitro model for the evaluation of human and animal drug metabolism and enzyme induction. Drug Metabolism Reviews 32:81-118.
35. Heringa MB, Hermens JLM. 2003. Measurement of free concentrations using negligible depletion-solid phase microextraction (ND-SPME). Trends in Analytical Chemistry 22:575-587.
36. Hewitt NJ, Lechon MJ, Houston JB, Hallifax D, Brown HS, Maurel P, Kenna JG, Gustavsson L, Lohmann C, et al. 2007. Primary hepatocytes: Current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metabolism Reviews 39:159-234.
37. Houston JB. 1994. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochemistry and Pharmacology 47:1469-1479.
38. Houston JB, Galetin A. 2003. Progress towards prediction of human pharmacokinetic parameters from in vitro technologies. Drug Metabolism Reviews 35:393-415.
39. Hukkanen J, Lassila A, Paivarinta K, Valanne S, Sarpo S, Hakkola J, Pelkonen O, Raunio H. 2000. Induction and regulation of xenobiotic-metabolizing cytochrome P450s in the human A549 lung adenocarcinoma cell line. American Journal of Respiratory Cell and Molecular Biology 22:360-366.
40. Hutzler M, Messing DM, Wienkers LC. 2005. Predicting drug-drug interactions in drug discovery: Where are we now and where are we going?. Current Opinions in Drug Discovery Development 8:51-58.
41. Ito K, Brown HS, Houston JB. 2004. Database analyses for the prediction of in vivo drug-drug interactions from in vitro data. British Journal of Clinical Pharmacology 57:473-486.
42. Ito K, Houston JB. 2004. Comparison of the use of liver models for predicting drug clearance using in vitro kinetic data from hepatic microsomes and isolated hepatocytes. Pharmacology Research 21:785-792.
43. Ito K, Houston JB. 2005. Prediction of human drug clearance from in vitro and preclinical data using physiologically based and empirical approaches. Pharmacology Research 22:103-112.
44. Ito K, Iwatsubo T, Kanamitsu S, Nakajima Y, Sugiyama Y. 1998. Quantitative prediction of in vivo drug clearance and drug interactions from in vitro data on metabolism, together with binding and transport. Annual Reviews in Pharmacology and Toxicology 38:461-499.
45. Iwatsubo T, Hirota N, Ooie T, Suzuki H, Shimada N, Chiba K, Ishizaki T, Green CE, Tyson CA, Sugiyama Y. 1997. Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacology and Therapy 73:147-171.
46. Johnson TN, Tucker GT, Tanner MS, Rostami-Hodjegan A. 2005. Changes in liver volume from birth to adulthood: A meta-analysis. Liver Transplantation 11:1481-1493.
47. Jover R, Bort R, Gomez-Lechon MJ, Castell JV. 1998. Re-expression of C/EBP alpha induces CYP2B6, CYP2C9 and CYP2D6 genes in HepG2 cells. FEBS Letters 431:227-230.
48. Kanamitsu S, Ito K, Sugiyama Y. 2000. Quantitative prediction of in vivo drug-drug interactions from in vitro data based on physiological pharmacokinetics: Use of maximum unbound concentration of inhibitor at the inlet to the liver. Pharmacology Research 17:336-343.
49. Kostrubsky VE, Ramachandran V, Venkataramanan R, Dorko K, Esplen JE, Zhang S, Sinclair JF, Wrighton SA, Strom SC. 1999. The use of human hepatocyte cultures to study the induction of cytochrome P-450. Drug Metabolism and Disposition 27:887-894.
50. Kremers P. 1999. Liver microsomes: A convenient tool for metabolism studies but.... In: Boobis AR, Kremers P, Pelkonen O, Pithan K, editors. European symposium on the prediction of drug metabolism in man: Progress and problems. Luxembourg: Office for Official Publications of the European Communities. pp 38-52.
51. Kremers P. 2002. In vitro tests for predicting drug-drug interactions: The need for validated procedures. Pharmacology and Toxicology 91:209-217.
52. Lave T, Dupin S, Schmitt C, Valles B, Ubeaud G, Chou RC, Jaeck D, Coassolo P. 1997. The use of human hepatocytes to select compounds based on their expected hepatic extraction ratios in humans. Pharmacology Research 14:152-155.
53. LeCluyse EL. 2001. Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation. European Journal of Pharmaceutical Science 13:343-368.
54. Le Vee M, Jigorel E, Glaise D, Gripon P, Guguen-Guillouzo C, Fardel O. 2006. Functional expression of sinusoidal and canalicular hepatic drug transporters in the differentiated human hepatoma HepaRG cell line. European Journal of Pharmaceutical Science 28:109-117.
55. Li AP, Maurel P, Gomez-Lechon MJ, Cheng LC, Jurima-Romet M. 1997. Preclinical evaluation of drug-drug interaction potential: Present status of the application of primary human hepatocytes in the evaluation of cytochrome P450 induction. Chemico-Biological Interactions 107:5-16.
56. Lin JH. 1995. Species similarities and differences in pharmacokinetics. Drug Metabolism and Disposition 23:1008-1021.
57. Lin JH, Lu AYH. 1997. Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacology Reviews 49:403-449.
58. Lombardo F, Obach RS, Shalaeva MY, Gao F. 2004. Prediction of human volume of distribution values for neutral and basic drugs. 2. Extended data set and leave-class-out statistics. Journal of Medical Chemistry 47:1242-1250.
59. McGinnity DF, Riley RJ. 2001. Predicting drug pharmacokinetics in humans from in vitro metabolism studies. Biochemistry Society Transactions 29:135-139.
60. McLure JA, Miners JO, Birkett DJ. 2000. Nonspecific binding of drugs to human liver microsomes. British Journal of Clinical Pharmacology 49:453-461.
61. Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y. 2003. Impact of drug transporter studies on drug discovery and development. Pharmacology Reviews 55:425-461.
62. Moody GC, Griffin SJ, Mather AN, McGinnity DF, Riley RJ. 1999. Fully automated analysis of activities catalysed by the major human liver cytochrome P450 (CYP) enzymes: Assessment of human CYP inhibition potential. Xenobiotica 29:53-75.
63. Murry DJ, Crom WR, Reddick WE, Bhargava R, Evans WE. 1995. Liver volume as a determinant of drug clearance in children and adolescents. Drug Metabolism and Disposition 23:1110-1116.
64. Nagilla R, Frank KA, Jolivette LJ, Ward KW. 2006. Investigation of the utility of published in vitro intrinsic clearance data for prediction of in vivo clearance. Journal of Pharmacology and Toxicology Methods 53:106-116.
65. Obach RS. 1997. Non-specific binding to microsomes: Impact on scale-up of in vitro intrinsic clearance to hepatic clearance as assessed through examination of warfarin, imipramine, and propranolol. Drug Metabolism and Disposition 25:1359-1369.
66. Obach RS. 1999. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metabolism and Disposition 27:1350-1359.
67. Obach RS. 2001. The prediction of human clearance from hepatic microsomal metabolism data. Current Opinions in Drug Discovery Development 4:36-44.
68. Ogilvie BW, Zhang D, Li W, Rodrigues AD, Gyason AE, Holsapple J, Toren P, Parkinson A. 2006. Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug metabolism and Disposition 34:191-197.
69. Oravcova J, Bohs B, Lindner W. 1996. Drug-protein binding sites. New trends in analytical and experimental methodology. Journal of Chromatography B: Biomedical Applications 677:1-28.
70. Pacifici GM, Viani A. 1992. Methods of determining plasma and tissue binding of drugs. Pharmacokinetic consequences. Clinical Pharmacokinetics 23:449-468.
71. Pacifici GM, Pelkonen O, editors. 2001. Variation of drug metabolism in humans. London: Taylor & Francis.
72. Palmgren JJ, Monkkonen J, Korjamo T, Hassinen A, Auriola S. 2006. Drug adsorption to plastic containers and retention of drugs in cultured cells under in vitro conditions. European Journal of pharmaceutics and Biopharmaceutics 64:369-378.
73. Parent R, Marion MJ, Furio L, Trepo C, Petit MA. 2004. Origin and characterization of a human bipotent liver progenitor cell line. Gastroenterology 126:1147-1156.
74. Pearce RE, McIntyre CJ, Madan A, Sanzgiri U, Draper AJ, Bullock PL, Cook DC, Burton LA, Latham J, et al. 1996. Effects of freezing, thawing, and storing human liver microsomes on cytochrome P450 activity. Archives of Biochemistry and Biophysics 331:145-169.
75. Pelkonen O, Boobis AR, Gundert-Remy U. 2001. In vitro prediction of gastrointestinal absorption and bioavailability: An experts' meeting report. European Journal of Clinical Pharmacology 57:621-629.
76. Pelkonen O, Taavitsainen P, Rautio A, Raunio H, Mäenpää J. 1998. Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica 28:1203-1253.
77. Pelkonen O, Turpeinen M, Uusitalo J, Rautio A, Raunio H. 2005. Prediction of drug metabolism and interactions on the basis of in vitro investigations. Basic Clinical Pharmacology and Toxicology 96:167-175.
78. Perrett H, Barter Z, Jones B, Yamazaki H, Tucker G, Rostami-Hodjegan A. 2007. Disparity in holo/apoprotein ratios of different standards used for immuno-quantification of hepatic cytochrome P450 enzymes. Drug Metabolism and Disposition DOI: 10.1124/dmd.107.015743.
79. Reinoso RF, Telfer BA, Brennan BS, Rowland M. 2001. Uptake of teitoplanin by isolated rat hepatocytes: comparison with in vivo hepatic distribution. Drug Metabolism and Disposition 29:453-459.
80. Renwick AB, Watts PS, Edwards RJ, Barton PT, Guyonnet I, Price RJ, Tredger JM, Pelkonen O, Boobis AR, Lake BG. 2000. Differential maintenance of cytochrome P450 enzymes in cultured precision-cut human liver slices. Drug Metabolism and Disposition 28:1202-1209.
81. Riley RJ, McGinnity DF, Austin RP. 2005. A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes. Drug Metabolism and Disposition 33:1304-1311.
82. Rodrigues AD. 1999. Integrated cytochrome P450 reaction phenotyping: Attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes. Biochemistry and Pharmacology 57:465-480.
83. Rodrigues AD, Lin JH. 2001. Screening of drug candidates for their drug-drug interaction potential. Current Opinions in Chemistry and Biology 5:396-401.
84. Rostami-Hodjegan A, Tucker GT. 2007. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nature Reviews Drug Discovery 6:140-148.
85. Rowland M, Tozer TN. 1994. Clinical pharmacokinetics: Concepts and applications. 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins.
86. Rowland Yeo K, Rostami-Hodjegan A, Tucker GT. 2004. Abundance of cytochromes P450 in human liver: A meta-analysis. British Journal of Clinical Pharmacology 57:687-688.
87. Shibata Y, Takahashi H, Chiba M, Ishii Y. 2002. Prediction of hepatic clearance and availability by cryopreserved human hepatocytes: An application of serum incubation method. Drug Metabolism and Disposition 30:892-896.
88. Shiran MR, Proctor NJ, Howgate EM, Rowland-Yeo K, Tucker GT, Rostami-Hodjegan A. 2006. Prediction of metabolic drug clearance in humans: In vitro-in vivo extrapolation versus allometric scaling. Xenobiotica 36:567-580.
89. Shitara Y, Horie T, Sugiyama Y. 2006. Transporters as a determinant of drug clearance and tissue distribution. European Journal of Pharmaceutical Science 27:425-446.
90. Soares MG, Grime K, Sproston JL, Webborn PJ, Riley RJ. 2007. Use of hepatocytes to assess the contribution of hepatic uptake to clearance in vivo. Drug Metabolism and Disposition 35:859-865.
91. Theil FP, Guentert TW, Haddad S, Poulin P. 2003. Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection. Toxicology Letters 138:29-49.
92. Treiber A, Schneiter R, Delahaye S, Clozel M. 2004. Inhibition of organic anion transporting polypeptide-mediated hepatic uptake is the major determinant in the pharmacokinetic interaction between bosentan and cyclosporin A in the rat. Journal of Pharmacology and Experimental Therapy 308:1121-1129.
93. Turpeinen M, Uusitalo J, Jalonen J, Pelkonen O. 2005. Multiple P450 substrates in a single run: Rapid and comprehensive in vitro interaction assay. European Journal of Pharmaceutical Science 24:123-132.
94. Urata K, Kawasaki S, Matsunami H, Hashikura Y, Ikegami T, Ishizone S, Momose Y, Komiyama A, Makuuchi M. 1995. Calculation of child and adult standard liver volume for liver transplantation. Hepatology 21:1317-1321.
95. Van de Waterbeemd H. 2005a. Which in vitro screens guide the prediction of oral absorption and volume of distribution? Basic Clinical Pharmacology and Toxicology 96:162-166.
96. Van de Waterbeemd H. 2005b. From in vivo to in vitro/in silico ADME: Progress and challenges. Expert Opinions in Drug Metabolism and Toxicology 1:1-4.
97. VandenBranden M, Wrighton SA, Ekins S, Gillespie JS, Binkley SN, Ring BJ, Gadberry MG, Mullins DC, Strom SC, Jensen CB. 1998. Alterations of the catalytic activities of drug-metabolizing enzymes in cultures of human liver slices. Drug Metabolism and Disposition 26:1063-1068.
98. Vickers AE. 1994. Use of human organ slices to evaluate the biotransformation and drug-induced side-effects of pharmaceuticals. Cell Biology and Toxicology 10:407-414.
99. Von Bahr C, Groth CG, Jansson H, Lundgren G, Lind M, Glaumann H. 1980. Drug metabolism in human liver in vitro: Establishment of a human liver bank. Clinical Pharmacology and Therapy 27:711-725.
100. Walsky RL, Obach RS. 2004. Validated assays for human cytochrome P450 activities. Drug Metabolism and Disposition 32:647-660.
101. Worboys PD, Carlile DJ. 2001. Implications and consequences of enzyme induction on preclinical and clinical drug development. Xenobiotica 31:539-556.
102. Worboys PD, Bradbury A, Houston JB. 1996. Kinetics of drug metabolism in rat liver slices. II. Comparison of clearance by liver slices and freshly isolated hepatocytes. Drug Metabolism and Disposition 24:676-681.
103. Worboys PD, Bradbury A, Houston JB. 1997. Kinetics of drug metabolism in rat liver slices. III. Relationship between metabolic clearance and slice uptake rate. Drug Metabolism and Disposition 25:460-467.
104. Yamano K, Yamamoto K, Kotaki H, Takedomi S, Matsuo H, Sawada Y, Iga T. 1999. Correlation between in vivo and in vitro hepatic uptake of metabolic inhibitors of cytochrome P-450 in rats. Drug Metabolism and Disposition 27:1225-1231.
105. Yamano K, Yamamoto K, Kotaki H, Takedomi S, Matsuo H, Sawada Y, Iga T. 2000. Quantitative prediction of metabolic inhibition of midazolam by erythromycin, diltiazem, and verapamil in rats: Implication of concentrative uptake of inhibitors into liver. Journal of Pharmacology and Experimental Therapy 292:1118-1126.
106. Yamazaki H, Inoue K, Turvy CG, Guengerich FP, Shimada T. 1997. Effects of freezing, thawing, and storage of human liver samples on the microsomal contents and activities of cytochrome P450 enzymes. Drug Metabolism and Disposition 25:168-174.
107. Yan Z, Caldwell GW. 2001. Metabolism profiling, and cytochrome P450 inhibition, induction in drug discovery. Current Topics in Medicine and Chemistry 1:403-425.
108. Yang J, Jamei M, Yeo KR, Rostami-Hodjegan A, Tucker GT. 2007. Misuse of the well-stirred model of hepatic drug clearance. Drug Metabolism and Disposition 35:501-502.
109. Yoshitomi S, Ikemoto K, Takahashi J, Miki H, Namba M, Asahi S. 2001. Establishment of the transformants expressing human cytochrome P450 subtypes in HepG2, and their applications on drug metabolism and toxicology. Toxicology In Vitro 15:245-256.