In Vitro Metabolism in Preclinical Drug Development

Preclinical Development Handbook: ADME and Biopharmaceutical Properties

Volumn , Issue , 2008, Pages 743-774

  Pelkonen, Olavi ^a   Tolonen, Ari ^a,b   Turpeinen, Miia ^a   Uusitalo, Jouko ^b  

^a UNIVERSITY OF OULU   (Finland)

^b Novamass Analytical Ltd   (Finland)

Author keywords

Enzyme kinetic characterization; Enzyme selective substrates, inhibitors, and antibodies; Principal metabolic reactions

Indexed keywords

EID: 79956357782     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9780470249031.ch21     Document Type: Chapter

References (101)

1. Pelkonen O, Raunio H. In vitro screening of drug metabolism during drug development:Can we trust the predictions? Expert Opin Drug Metab Toxicol 2005;1:49-60.
2. Lin JH, Lu AYH. Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol Rev 1997;49:403-449.
3. Van de Waterbeemd H, Gifford E. ADMET in silico modelling:towards prediction paradise? Nat Rev Drug Dev 2003;2:192-203.
4. Guengerich FP, Rendic S. Human cytochrome P450 enzymes(human CYPs):human cytochrome P450 enzymes, a status report summarizing their reactions, substrates, inducers, and inhibitors-1st update. Drug Metab Rev 2002;34:1-450.
5. Coecke S, Ahr H, Blaauboer BJ, Bremer S, Casati S, Castell J, Combes R, Corvi R, Crespi CL, Cunningham ML, Elaut G, Eletti B, Freidig A, Gennari A, Ghersi-Egea JF, Guillouzo A, Hartung T, Hoet P, Ingelman-Sundberg M, Munn S, Janssens W, Ladstetter B, Leahy D, Long A, Meneguz A, Monshouwer M, Morath S, Nagelkerke F, Pelkonen O, Ponti J, Prieto P, Richert L, Sabbioni E, Schaack B, Steiling W, Testai E, Vericat JA, Worth A. Metabolism:a bottleneck in in vitro toxicological test development. The Report and Recommendations of ECVAM Workshop 54. Altern Lab Anim 2006;34:49-84.
6. Pelkonen O, Baumann A, Reichel A. Pharmacokinetic Challenges in Drug Discovery. Ernst Schering Research Foundation Workshop 37. Berlin:Springer; 2002.
7. Kremers P. Liver microsomes:a convenient tool for metabolism studies but.... In B oobis AR, Kremers P, Pelkonen O, Pithan K, Eds. E uropean Symposium on the Prediction of Drug Metabolism in Man:Progress and Problems. Office for Official Publications of the European Communities; 1999, pp 38-52.
8. Rodrigues AD. Integrated cytochrome P450 reaction phenotyping:attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes. Biochem Pharmacol 1999;57:465-480.
9. Guillouzo A. Acquisition and use of human in vitro liver preparations. Cell Biol Toxicol 1995;11:141-145.
10. Guillouzo A, Morel F, Fardel O, Meunier B. Use of human hepatocyte cultures for drug metabolism studies. Toxicology 1993;82:209-219.
11. Ferrero JL, Brendel K. Liver slices as a model in drug metabolism. Adv Pharmacol 1997;43:131-169.
12. Allen DD, Caviedes R, Cardenas AM, Shimahara T, Segura-Aguilar J, Caviedes PA. Cell lines as in vitro models for drug screening and toxicity studies. Drug Dev Ind Pharm 2005;31:757-768.
13. Brandon EFA, Raap CD, Meijerman I, Beijnen JH, Schellens JHM. An update on in vitro test methods in human hepatic drug biotransformation research:pros and cons. Toxicol Appl Pharmacol 2003;189:233-246.
14. Plant N. Strategies for using in vitro screens in drug metabolism. DDT 2004;9:328-336.
15. Gomez-Lechon MJ, Donato MT, Castell JV, Jover R. Human hepatocytes in primary culture:the choice to investigate drug metabolism in man. Curr Drug Metab 2004;5:443-462.
16. Andersson TB, Sjöberg H, Hoffmann K-J, Boobis AR, Watts P, Edwards RJ, Lake BG, Price RJ, Renwick AB, Gómez-Lechón MJ, Castell JV, Ingelman-Sundberg M, Hidestrand M, Goldfarb PS, Lewis DFV, Corcos L, Guillouzo A, Taavitsainen P, Pelkonen O. An assessment of human liver-derived in vitro systems to predict the in vivo metabolism and clearance of almokalant. Drug Metab Dispos 2001;29:712-720.
17. Salonen JS, Nyman L, Boobis AR, Edwards RJ, Watts P, Lake BG, Price RJ, Renwick AB, Gómez-Lechón MJ, Castell JV, Ingelman-Sundberg M, Hidestrand M, Guillouzo A, Corcos L, Goldfarb PS, Lewis DFV, Taavitsainen P, Pelkonen O. Comparative studies on the CYP-associated metabolism and interaction potential of selegiline between human liver-derived in vitro systems. Drug Metab Dispos 2003;31:1093-1102.
18. Pelkonen O, Myllynen P, Taavitsainen P, Boobis AR, Watts P, Lake BG, Price RJ, Renwick AB, Gómez-Lechón MJ, Castell JV, Ingelman-Sundberg M, Hidestrand M, Guillouzo A, Corcos L, Goldfarb PS, Lewis DFV. Carbamazepine:a "blind "assessment of CYP-associated metabolism and interactions in human liver-derived in vitro systems. Xenobiotica 2001;31:321-343.
19. Thompson TN. Early ADME in support of drug discovery:the role of metabolic stability studies. Curr Drug Metab 2000;1:215-241.
20. Gebhardt R, Hengstler JG, Muller D, Glockner R, Buenning P, Laube B, Schmelzer E, Ullrich M, Utesch D, Hewitt N, Ringel M, Hilz BR, Bader A, Langsch A, Koose T, Burger HJ, Maas J, Oesch F. New hepatocyte in vitro systems for drug metabolism:metabolic capacity and recommendations for application in basic research and drug development, standard operation procedures. Drug Metab Rev 2003;35:145-213.
21. Masimirembwa CM, Bredberg U, Andersson TB. Metabolic stability for drug discovery and development:pharmacokinetic and biochemical challenges. Clin Pharmacokinet 2003;42:515-528.
22. Ansede JH, Thakker DR. High-throughput screening for stability and inhibitory activity of compounds toward cytochrome P450-mediated metabolism. J Pharm Sci 2004;93:239-255.
23. Obach RS, Baxter JG, Liston TE, Silber BM, Jones BC, MacIntyre F, Rance DJ, Wastall P. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther 1999;283:46-58.
24. Clarke SE, Jeffrey P. Utility of metabolic stability screening:comparison of in vitro and in vivo clearance. Xenobiotica 2001;31:591-598.
25. Pelkonen O, Hukkanen J, Honkakoski P, Hakkola J, Viitala P, Raunio H. In vitro screening of cytochrome P450 induction potential. In Pelkonen O, Baumann A, Reichel A, Eds. Pharmacokinetics Challenges in Drug Discovery. Ernst Schering Research Foundation Workshop 37. Berlin:Springer Verlag; 2002, pp 105-137.
26. Honkakoski P, Negishi M. Regulation of cytochrome P450 (CYP) genes by nuclear receptors. Biochem J 2000;347:321-337.
27. Honkakoski P. Nuclear receptors CAR and PXR in metabolism and elimination of drugs. Curr Pharmacogenomics 2003;1:75-85.
28. Lindberg RL, Negishi M. Alteration of mouse cytochrome P450coh substrate specificity by mutation of a single amino-acid residue. Nature 1989;339:632-634.
29. Pelkonen O, Breimer DD. Role of environmental factors in the pharmacokinetics of drugs:considerations with respect to animal models, P-450 enzymes, and probe drugs. In Welling PG, Balant LP, Eds. Handbook of Experimental Pharmacology, Volume 110. Berlin:Springer-Verlag; 1994, pp 289-332.
30. Friedman MA, Woodcock J, Lumpkin MM, Shuren JE, Hass AE, Thompson LJ. The safety of newly approved medicines:do recent market removals mean there is a problem? JAMA 1999;281:1728-1734.
31. Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002;287:2215-2220.
32. Turpeinen M, Uusitalo J, Jalonen J, Pelkonen O. Multiple P450 substrates in a single run:rapid and comprehensive in vitro interaction assay. Eur J Pharm Sci 2005;24:123-132.
33. Tucker GT, Houston JB, Huang S-M. EUFEPS Conference Report. Optimising drug development:strategies to assess drug metabolism/transporter interaction potential-towards a consensus. Eur J Pharm Sci 2001;13:417-428.
34. Yuan R, Madani S, Wei X-X, Reynolds K, Huang S-M. Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions. Drug Metab Dispos 2002;30:1311-1319.
35. Walsky RL, Obach RS. Validated assays for human cytochrome P450 activities. Drug Metab Dispos 2004;32:647-660.
36. Streetman DS, Bertino JS Jr, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults:a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 2000;10:187-216.
37. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 1997;32:210-258.
38. Kremers P. In vitro tests for predicting drug-drug interactions:the need for validated procedures. Pharmacol Toxicol 2002;91:209-217.
39. Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A, Raunio H. Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica 1998;28:1203-1253.
40. Pelkonen O. Human CYPs:in vivo and clinical aspects. Drug Metab Rev 2000;34:37-46.
41. Pelkonen O, Turpeinen M, Uusitalo J, Rautio A, Raunio H. Prediction of drug metabolism and interactions on the basis of in vitro investigations. Basic Clin Pharmacol Toxicol 2005;96:167-175.
42. Lewis DF. Human cytochromes P450 associated with the phase 1 metabolism of drugs and other xenobiotics:a compilation of substrates and inhibitors of the CYP1, CYP2 and CYP3 families. Curr Med Chem 2003;10:1955-1972.
43. Ingelman-Sundberg M. Pharmacogenetics of cytochrome P 450 and its applications in drug therapy:the past, present and future. Trends Pharmacol Sci 2004;25:193-200.
44. Totah RA, Rettie AE. Cytochrome P450 2C8:substrates, inhibitors, pharmacogenetics, and clinical relevance. Clin Pharm Ther 2005;77:341-352.
45. Rowland Yeo K, Rostami-Hodjegan A, Tucker GT. Abundance of cytochromes P450 in human liver:a meta analysis. Br J Clin Pharmacol 2004;57:687-688.
46. Friedberg T, Henderson CJ, Pritchard MP, Wolf CR. In vivo and in vitro recombinant DNA technology as a powerful tool in drug development. In Woolf TF, Ed. Handbook of Drug Metabolism. New York:Marcel Dekker; 1999, pp 322-362.
47. Moody GC, Griffin SJ, Mather AN, McGinnity DF, Riley RJ. Fully automated analysis of activities catalysed by the major human liver cytochrome P450 (CYP) enzymes:assessment of human CYP inhibition potential. Xenobiotica 1999;29:53-75.
48. McGinnity DF, Riley RJ. Predicting drug pharmacokinetics in humans from in vitro metabolism studies. Biochem Soc Trans 2001;29(Pt 2):135-139.
49. Galetin A, Brown C, Hallifax D, Ito K, Houston JB. Utility of recombinant enzyme kinetics in prediction of human clearance:impact of variability, CYP3A5, and CYP2C19 on CYP3A4 probe substrates. Drug Metab Dispos 2004;32:1411-1420.
50. Nassar A-EF, Talaat RE. Strategies for dealing with metabolite elucidation in drug discovery and development. DDT 2004;9:317-327.
51. Kostiainen R, Kotiaho T, Kuuranne T, Auriola S. Liquid chromatography/atmospheric pressure ionization-mass spectrometry in drug metabolism studies. J Mass Spectrom 2003;38:357-372.
52. Cole MJ, Janiszewski JS, Fouda HG. Electrospray mass spectrometry in contemporary drug metabolism and pharmacokinetics. In Pramanik BN, Ganguly AK, Gross ML, Eds. Applled Electrospray Mass Spectrometry. New York:Marcel Dekker; 2002, pp 211-249.
53. Lee MS, Kerns EH. LC/MS applications in drug development. Mass Spectrom Rev 1999;18:187-279.
54. Tolonen A, Turpeinen M, Uusitalo J, Pelkonen O. A simple method for differentiation of monoisotropic drug metabolites with hydrogen-deuterium exchange LC/MS. Eur J Pharm Sci 2005;25:155-162.
55. Pellecchia M, Sem DS, Wutrich K. NMR in drug discovery. Nat Rev Drug Discov 2002;1:211-219.
56. Keifer PA. NMR spectroscopy in drug discovery:tools for combinatorial chemistry, natural products, and metabolism research. Prog Drug Res 2000;55:137-211.
57. Corcoral O, Spraul M. LC-NMR-MS in drug discovery. Drug Discov Today 2003;8:624-631.
58. Zhang N, Fountain ST, Bi H, Rossi DT. Quantification and rapid metabolite identification in drug discovery using API time-of-flight LC/MS. Anal Chem 2000;72:800-806.
59. Plumb RS, Stumpf CL, Granger JH, Castro-Perez J, Haselden JN, Dear GJ. Use of liquid chromatography/time-of-flight mass spectrometry and multivariate statistical analysis shows promise for the detection of drug metabolites in biological fluids. Rapid Commun Mass Spectrom 2003;17:2632-2638.
60. March RE, Todd JFJ, Eds. Practical Aspects of Ion Trap Mass Spectrometry. Boca Raton, FL:CRC Press; 1995.
61. Kantharaj E, Tuytelaars A, Proost PEA, Ongel Z, van Assouw HP, Gilissen RAHJ. Simultaneous measurement of drug metabolic stability and identification of metabolites using ion-trap mass spectrometry. Rapid Commun Mass Spectrom 2003;17:2661-2668.
62. Brewer E, Henion J. Atmospheric pressure ionization LC/MS/MS techniques for drug disposition studies. J Pharm Sci 1998;87:395-402.
63. Xu X, Veals J, Korfmacher WA. Comparison of conventional and enhanced mass resolution triple-quadrupole mass spectrometers for discovery bioanalytical applications. Rapid Commun Mass Spectrom 2003;17:832-837.
64. Hopfgartner G, Varesio E, Tschappat V, Grivet C, Bourgogne E, Leuthold LA. Triple quadrupole linear ion trap mass spectrometer for the analysis of small molecules and macromolecules. J Mass Spectrom 2004;39:845-855.
65. n capabilities. Rapid Commun Mass Spectrom 2001;15:1777-1795.
66. Hu Q, Noll RJ, Li H, Makarov A, Hardman M, Cooks RG. The Orbitrap:a new mass spectrometer. J Mass Spectrom 2005;40:430-443.
67. Marshall AG, Hendrickson CL, Jackson GS. Fourier transform ion cyclotron resonance mass spectrometry:a primer. Mass Spectrom Rev 1998;17:1-35.
68. Park BK, Kitteringham NR, Maggs JL, Pirmohamed M, Williams DP. The role of metabolic activation in drug-induced hepatotoxicity. Annu Rev Pharmacol Toxicol 2005;45:177-202.
69. Walgren JL, Mitchell MD, Thompson DC. Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol 2005;35:325-361.
70. Zhou S, Chan E, Duan W, Huang M, Chen Y-Z. Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metab Rev 2005;1:41-213.
71. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005;4:489-499.
72. Baillie TA, Cayen MN, Fouda H, Gerson RJ, Green JD, Grossman SJ, Klunk LJ, LeBlanc B, Perkins DG, Shipley LA. Contemporary issues in toxicology. Drug metabolites in safety testing. Toxicol Appl Pharmacol 2002;182:188-196.
73. Baillie TA. Future of toxicology-metabolic activation and drug design:challenges and opportunities in chemical toxicology. Chem Res Toxicol 2006;19:889-893.
74. Halpert JR. Structural basis of selective cytochrome P450 inhibition. Annu Rev Pharmacol Toxicol 1995;35:29-53.
75. Kent UM, Juschyshyn MI, Hollenberg PF. Mechanism-based inactivators as probes of cytochrome P450 structure and function. Curr Drug Metab 2001;2:215-243.
76. Sesardic D, Boobis AR, Murray BP, Murray S, Segura J, de la Torre R, Davies DS. Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in man. Br J Clin Pharmacol 1990;29:651-663.
77. Kunze KL, Trager WF. Isoform-selective mechanism-based inhibition of human cytochrome P450 1A2 by furafylline. Chem Res Toxicol 1993;6:649-656.
78. Back DJ, Houlgrave R, Tjia JF, Ward S, Orme ML. Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes. J Steroid Biochem Mol Biol 1991;38:219-225.
79. Turpeinen M, Nieminen R, Juntunen T, Taavitsainen P, Raunio H, Pelkonen O. Selective inhibition of CYP2B6-catalyzed bupropion hydroxylation in human liver microsomes in vitro. Drug Metab Dispos 2004;36:626-631.
80. Uetrecht J. Screening for the potential of a drug candidate to cause idiosyncratic drug reactions. DDT 2003;8:832-837.
81. Williams DP, Park BK. Idiosyncratic toxicity:the role of toxicophores and bioactivation. DDT 2003;8:1044-1050.
82. Dennehy MK, Richards KAM, Wernke GR, Shyr GR, Liebler DC. Cytosolic and nuclear protein targets of thiol-reactive electrophiles. Chem Res Toxicol 2006;19:20-29.
83. Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA. Drug-protein covalent adducts:an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 2004;17:3-16.
84. van de Waterbeemd H. High-throughput and in silico techniques in drug metabolism and pharmacokinetics. Curr Opin Drug Discov Dev 2002;5:33-43.
85. Wunberg T, Hendrix M, Hillisch A, Lobell M, Meier H, Schmeck C, Wild H, Hinzen B. Improving the hit-to-lead process:data-driven assessment of drug-like and lead-like screening hits. Drug Discov Today 2006;11:175-180.
86. Castro-Perez J, Plumb R, Granger JH, Beattie I, Joncour K, Wright A. Increasing throughput and information content for in vitro drug metabolism experiments using ultra-performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer. Rapid Commun Mass Spectrom 2005;19:843-848.
87. Lopez LL, Yu X, Cui D, Davis MR. Identification of drug metabolites in biological matrices by intelligent automated liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 1999;12:1756-1760.
88. Houston JB. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 1994;47:1469-1479.
89. Iwatsubo T, Hirota N, Ooie T, Suzuki H, Shimada N, Chiba K, Ishizaki T, Green CE, Tyson CA, Sugiyama Y. Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol Ther 1997;73:147-171.
90. Ito K, Iwatsubo T, Kanamitsu S, Nakajima Y, Sugiyama Y. Quantitative prediction of in vivo drug clearance and drug interactions from in vitro data on metabolism, together with binding and transport. Annu Rev Pharmacol Toxicol 1998;38:461-499.
91. Obach RS. 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 Metab Dispos 1999;27:1350-1359.
92. Obach RS. The prediction of human clearance from hepatic microsomal metabolism data. Curr Opin Drug Discov Dev 2001;4:36-44.
93. Rowland M, Tozer TN. Clinical Pharmacokinetics:Concepts and Applications, 3rd ed. Philadelphia:Lippincott Williams & Wilkins; 1994.
94. Houston JB, Galetin A. Progress towards prediction of human pharmacokinetic parameters fron in vitro technologies. Drug Metab Rev 2003;35:393-415.
95. Shiran MR, Proctor NJ, Howgate EM, Rowland-Yeo K, Tucker GT, Rostami-Hodjegan A. Prediction of metabolic drug clearance in humans:in vitro-in vivo extrapolation vs allometric scaling. Xenobiotica 2006;36:567-580.
96. Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, Kumar G, McLeod J, Obach RS, Roberts S, Roe A, Shah A, Snikeris F, Sullivan JT, Tweedie D, Vega JM, Walsh J, Wrighton SA. The conduct of in vitro and in vivo drug-drug interaction studies:a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos 2003;31:815-832.
97. Ito K, Brown HS, Houston JB. Database analyses for the prediction of in vivo drug-drug interactions from in vitro data. Br J Clin Pharmacol 2004;57:473-486.
98. Obach RS, Walsky RL, Venkatakrishnan K, Gaman EA, Houston JB, Tremaine LM. The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions. J Pharmacol Exp Ther 2006;316:336-348.
99. Hartung T, Bremer S, Casati S, Coecke S, Corvi R, Fortaner S, Gribaldo L, Halder M, Hoffmann S, Roi AJ, Prieto P, Sabbioni E, Scott L, Worth A, Zuang V. A modular approach to the ECVAM principles on test validity. Altern Lab Anim 2004;32:467-472.
100. Aninat C, Piton A, Glaise D, Le Charpentier T, Langouet S, Morel F, Guguen-Guillouzo C, Guillouzo A. Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab Dispos 2006;34:75-83.
101. Le Vee M, Jigorel E, Glaise D, Gripon P, Guguen-Guillouzo C, Fardel O. F unctional expression of sinusoidal and canalicular hepatic drug transporters in the differentiated human hepatoma HepaRG cell line. Eur J Pharm Sci 2006;28:109-117.