The Evolving Role of Drug Metabolism in Drug Discovery and Development

  • Lilian G. Yengi
  • Louis Leung
  • John Kao
Expert Review


Drug metabolism in pharmaceutical research has traditionally focused on the well-defined aspects of absorption, distribution, metabolism and excretion, commonly-referred to ADME properties of a compound, particularly in the areas of metabolite identification, identification of drug metabolizing enzymes (DMEs) and associated metabolic pathways, and reaction mechanisms. This traditional emphasis was in part due to the limited scope of understanding and the unavailability of in vitro and in vivo tools with which to evaluate more complex properties and processes. However, advances over the past decade in separate but related fields such as pharmacogenetics, pharmacogenomics and drug transporters, have dramatically shifted the drug metabolism paradigm. For example, knowledge of the genetics and genomics of DMEs allows us to better understand and predict enzyme regulation and its effects on exogenous (pharmacokinetics) and endogenous pathways as well as biochemical processes (pharmacology). Advances in the transporter area have provided unprecedented insights into the role of transporter proteins in absorption, distribution, metabolism and excretion of drugs and their consequences with respect to clinical drug–drug and drug–endogenous substance interactions, toxicity and interindividual variability in pharmacokinetics. It is therefore essential that individuals involved in modern pharmaceutical research embrace a fully integrated approach and understanding of drug metabolism as is currently practiced. The intent of this review is to reexamine drug metabolism with respect to the traditional as well as current practices, with particular emphasis on the critical aspects of integrating chemistry and biology in the interpretation and application of metabolism data in pharmaceutical research.

Key words

drug discovery and development drug interactions clearance drug metabolism exposure idiosyncratic drug toxicity inhibition integration of emerging sciences pharmacogenetics pharmacogenomics transporters 



The authors would like to thank Dr Julius Enoru-Eta and Dr Joann Scatina for their review of this manuscript.


  1. 1.
    J. Axelrod. The enzymatic deamination of amphetamine (benzedrine) J. Biol. Chem. 214:753–763 (1955).PubMedGoogle Scholar
  2. 2.
    R. I. Dorfman, J. W. Cook, and J. B. Hamilton. Conversion by the human of the testis hormone, testosterone, into the urinary androgen, androsterone J. Biol. Chem. 130:285–295 (1939).Google Scholar
  3. 3.
    E. C. Miller, J. A. Miller, R. R. Brown, and J. C. Macdonald. On the protective action of certain polycyclic aromatic hydrocarbons against carcinogenesis by aminoazo dyes and 2-acetylaminofluorene Cancer Res. 18:469–477 (1958).PubMedGoogle Scholar
  4. 4.
    G. C. Mueller and J. A. Miller. The metabolism of 4-dimethylaminoazobenzene by rat liver homogenates J. Biol. Chem. 176:535–544 (1948).PubMedGoogle Scholar
  5. 5.
    G. C. Mueller and J. A. Miller. The metabolism of methylated aminoazo dyes. II. Oxidative demethylation by rat liver homogenates J. Biol. Chem. 202:579–587 (1953).PubMedGoogle Scholar
  6. 6.
    K. J. Ryan. Conversion of androstenedione to estrone by placental microsomes Biochim. Biophys. Acta 27:658–659 (1958).PubMedGoogle Scholar
  7. 7.
    R. T. Williams Detoxication Mechanisms: The Metabolism of Drugs and Allied Organic Compounds, Chapman and Hall, London, 1949.Google Scholar
  8. 8.
    R. T. Williams Detoxication Mechanisms: The Metabolism and Detoxication of Drugs, Toxic Substances, and Other Organic Compounds, Chapman and Hall, London, 1959.Google Scholar
  9. 9.
    P. D. Josephy, F. P. Guengerich, and J. O. Miners. Phase I and II drug metabolism: terminology that we should phase out? Drug Metab. Rev. 37:575–580 (2005).Google Scholar
  10. 10.
    H. S. Mason. Mechanisms of oxygen metabolism Science 125:1185–1188 (1957).PubMedGoogle Scholar
  11. 11.
    D. Y. Cooper, S. Levin, S. Narasimhulu, and O. Rosenthal. Photochemical action spectrum of the terminal oxidase of mixed function oxidase systems Science 147:400–402 (1965).PubMedGoogle Scholar
  12. 12.
    T. Omura and R. Sato. A new cytochrome in liver microsomes J. Biol. Chem. 237:1375–1376 (1962).PubMedGoogle Scholar
  13. 13.
    R. W. Estabrook, D. Y. Cooper, and O. Rosenthal. The light reversible carbon monoxide inhibition of the steroid C21-hydroxylase system of the adrenal cortex Biochem. Z. 338:741–755 (1963).PubMedGoogle Scholar
  14. 14.
    A. Y. Lu and M. J. Coon. Role of hemoprotein P-450 in fatty acid omega-hydroxylation in a soluble enzyme system from liver microsomes J. Biol. Chem. 243:1331–1332 (1968).PubMedGoogle Scholar
  15. 15.
    R. W. Estabrook. A passion for P450s (rememberances of the early history of research on cytochrome P450) Drug Metab. Dispos. 31:1461–1473 (2003).PubMedGoogle Scholar
  16. 16.
    F. P. Guengerich. Cytochrome P450: what have we learned and what are the future issues? Drug Metab. Rev. 36:159–197 (2004).PubMedGoogle Scholar
  17. 17.
    D. A. Haugen, T. A. van der Hoeven, and M. J. Coon. Purified liver microsomal cytochrome P-450. Separation and characterization of multiple forms J. Biol. Chem. 250:3567–3570 (1975).PubMedGoogle Scholar
  18. 18.
    A. Hildebrandt, H. Remmer, and R. W. Estabrook. Cytochrome P-450 of liver microsomes-one pigment or many Biochem. Biophys. Res. Commun. 30:607–612 (1968).PubMedGoogle Scholar
  19. 19.
    D. W. Nebert. Multiple forms of inducible drug-metabolizing enzymes: a reasonable mechanism by which any organism can cope with adversity Mol. Cell. Biochem. 27:27–46 (1979).PubMedGoogle Scholar
  20. 20.
    N. E. Sladek and G. J. Mannering. Induction of drug metabolism. II. Qualitative differences in the microsomal N-demethylating systems stimulated by polycyclic hydrocarbons and by phenobarbital Mol. Pharmacol. 5:186–199 (1969).PubMedGoogle Scholar
  21. 21.
    P. B. Danielson. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans Curr. Drug Metab. 3:561–597 (2002).PubMedGoogle Scholar
  22. 22.
    S. D. Aust, D. L. Roerig, and T. C. Pederson. Evidence for superoxide generation by NADPH-cytochrome c reductase of rat liver microsomes Biochem. Biophys. Res. Commun. 47:1133–1137 (1972).PubMedGoogle Scholar
  23. 23.
    J. T. Groves and G. A. McClusky. Aliphatic hydroxylation by highly purified liver microsomal cytochrome P-450. Evidence for a carbon radical intermediate Biochem. Biophys. Res. Commun. 81:154–160 (1978).PubMedGoogle Scholar
  24. 24.
    F. P. Guengerich. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity Chem. Res. Toxicol. 14:611–650 (2001).PubMedGoogle Scholar
  25. 25.
    P. R. Ortiz de Montellano Oxygen Activation and Reactivity, Cytochrome P450: Structure, Mechanisms, and Biochemistry. Plenum, New York, 1995, pp. 243–303.Google Scholar
  26. 26.
    P. R. Ortiz de Montellano and J. J. De Voss. Substrate oxidation by cytochrome P450 enzymes. In P. R. O. d. Montellano (ed.), Cytochrome P450: Structure, Mechanisms, and Biochemistry, Plenum, New York, 2004, pp. 183–230.Google Scholar
  27. 27.
    R. A. Sheldon and J. K. Kochi Activation of Molecular Oxygen by Metal Complexes. Metal-catalyzed Oxidations of Organic Compounds. Academic, New York, 1981, pp. 108–112.Google Scholar
  28. 28.
    H. W. Strobel and M. J. Coon. Effect of superoxide generation and dismutation on hydroxylation reactions catalyzed by liver microsomal cytochrome P-450 J. Biol. Chem. 246:7826–7829 (1971).PubMedGoogle Scholar
  29. 29.
    S. Chen, J. E. Shively, S. Nakajin, M. Shinoda, and P. F. Hall. Amino terminal sequence analysis of human placenta aromatase Biochem. Biophys. Res. Commun. 135:713–719 (1986).PubMedGoogle Scholar
  30. 30.
    A. Mahgoub, J. R. Idle, L. G. Dring, R. Lancaster, and R. L. Smith. Polymorphic hydroxylation of Debrisoquine in man Lancet 2:584–586 (1977).PubMedGoogle Scholar
  31. 31.
    W. L. Miller. Congenital adrenal hyperplasia N. Engl. J. Med. 314:1321–1322 (1986).PubMedGoogle Scholar
  32. 32.
    D. W. Nebert and D. W. Russell. Clinical importance of the cytochromes P450 Lancet 360:1155–1162 (2002).PubMedGoogle Scholar
  33. 33.
    E. C. Miller and J. A. Miller. Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules Cancer 47:2327–2345 (1981).PubMedGoogle Scholar
  34. 34.
    U. Groth and H. G. Neumann. The relevance of chemico-biological interactions for the toxic and carcinogenic effects of aromatic amines. V. The pharmacokinetics of related aromatic amines in blood Chem. Biol. Interact. 4:409–419 (1972).PubMedGoogle Scholar
  35. 35.
    D. J. Jollow, J. R. Mitchell, W. Z. Potter, D. C. Davis, J. R. Gillette, and B. B. Brodie. Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo J. Pharmacol. Exp. Ther. 187:195–202 (1973).PubMedGoogle Scholar
  36. 36.
    W. Z. Potter, D. C. Davis, J. R. Mitchell, D. J. Jollow, J. R. Gillette, and B. B. Brodie. Acetaminophen-induced hepatic necrosis. 3. Cytochrome P-450-mediated covalent binding in vitro J. Pharmacol. Exp. Ther. 187:203–210 (1973).PubMedGoogle Scholar
  37. 37.
    I. Gardner, M. Popovic, N. Zahid, and J. P. Uetrecht. A comparison of the covalent binding of clozapine, procainamide, and vesnarinone to human neutrophils in vitro and rat tissues in vitro and in vivo Chem. Res. Toxicol. 18:1384–1394 (2005).PubMedGoogle Scholar
  38. 38.
    A. S. Kalgutkar, I. Gardner, R. S. Obach, C. L. Shaffer, E. Callegari, K. R. Henne, A. E. Mutlib, D. K. Dalvie, J. S. Lee, Y. Nakai, J. P. O’Donnell, J. Boer, and S. P. Harriman. A comprehensive listing of bioactivation pathways of organic functional groups Curr. Drug Metab. 6:161–225 (2005).PubMedGoogle Scholar
  39. 39.
    N. R. Pumford and N. C. Halmes. Protein targets of xenobiotic reactive intermediates Annu. Rev. Pharmacol. Toxicol. 37:91–117 (1997).PubMedGoogle Scholar
  40. 40.
    J. Uetrecht. Prediction of a new drug’s potential to cause idiosyncratic reactions Curr. Opin. Drug. Discov. Dev. 4:55–59 (2001).Google Scholar
  41. 41.
    S. Zhou, E. Chan, W. Duan, M. Huang, and Y. Z. Chen. Drug bioactivation, covalent binding to target proteins and toxicity relevance Drug Metab. Rev. 37:41–213 (2005).PubMedGoogle Scholar
  42. 42.
    E. Fontana, P. M. Dansette, and S. M. Poli. Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity Curr. Drug Metab. 6:413–454 (2005).PubMedGoogle Scholar
  43. 43.
    S. Zhou, E. Chan, L. Y. Lim, U. A. Boelsterli, S. C. Li, J. Wang, Q. Zhang, M. Huang, and A. Xu. Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4 Curr. Drug Metab. 5:415–442 (2004).PubMedGoogle Scholar
  44. 44.
    S. Zhou, S. Yung Chan, B. Cher Goh, E. Chan, W. Duan, M. Huang, and H. L. McLeod. Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs Clin. Pharmacokinet. 44:279–304 (2005).PubMedGoogle Scholar
  45. 45.
    M. Eichelbaum, M. Ingelman-Sundberg, and W. E. Evans. Pharmacogenomics and individualized drug therapy Annu. Rev. Med. 57:119–137 (2006).PubMedGoogle Scholar
  46. 46.
    G. S. Ginsburg, R. P. Konstance, J. S. Allsbrook, and K. A. Schulman. Implications of pharmacogenomics for drug development and clinical practice Arch. Intern. Med. 165:2331–2336 (2005).PubMedGoogle Scholar
  47. 47.
    D. B. Goldstein, S. K. Tate, and S. M. Sisodiya. Pharmacogenetics goes genomic Nat. Rev., Genet. 4:937–947 (2003).Google Scholar
  48. 48.
    D. W. Nebert. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Clin. Genet. 56:247–258 (1999).PubMedGoogle Scholar
  49. 49.
    A. Hedgecoe, and P. Martin. The drugs don’t work: expectations and the shaping of pharmacogenetics Soc. Stud. Sci. 33:327–364 (2003).PubMedGoogle Scholar
  50. 50.
    C. R. Wolf, G. Smith, and R. L. Smith. Science, medicine, and the future: Pharmacogenetics BMJ 320:987–990 (2000).PubMedGoogle Scholar
  51. 51.
    K. A. Frazer, L. Elnitski, D. M. Church, I. Dubchak, and R. C. Hardison. Cross-species sequence comparisons: a review of methods and available resources Genome Res. 13:1–12 (2003).PubMedGoogle Scholar
  52. 52.
    K. A. Frazer, J. B. Sheehan, R. P. Stokowski, X. Chen, R. Hosseini, J. F. Cheng, S. P. Fodor, D. R. Cox, and N. Patil. Evolutionarily conserved sequences on human chromosome 21 Genome Res. 11:1651–1659 (2001).PubMedGoogle Scholar
  53. 53.
    M. A. Higgins, B. R. Berridge, B. J. Mills, A. E. Schultze, H. Gao, G. H. Searfoss, T. K. Baker, and T. P. Ryan. Gene expression analysis of the acute phase response using a canine microarray Toxicol. Sci. 74:470–484 (2003).PubMedGoogle Scholar
  54. 54.
    N. Kato, M. Shibutani, H. Takagi, C. Uneyama, K. Y. Lee, S. Takigami, K. Mashima, and M. Hirose. Gene expression profile in the livers of rats orally administered ethinylestradiol for 28 days using a microarray technique Toxicology 200:179–192 (2004).PubMedGoogle Scholar
  55. 55.
    G. H. Searfoss, W. H. Jordan, D. O. Calligaro, E. J. Galbreath, L. M. Schirtzinger, B. R. Berridge, H. Gao, M. A. Higgins, P. C. May, and T. P. Ryan. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor J. Biol. Chem. 278:46107–46116 (2003).PubMedGoogle Scholar
  56. 56.
    B. Alexanderson, D. A. Evans, and F. Sjoqvist. Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy Br. Med. J. 4:764–768 (1969).PubMedGoogle Scholar
  57. 57.
    W. Hammer, and F. Sjoqvist. Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds Life Sci. 6:1895–1903 (1967).PubMedGoogle Scholar
  58. 58.
    M. Eichelbaum. Polymorphic oxidation of debrisoquine and sparteine Prog. Clin. Biol. Res. 214:157–167 (1986).PubMedGoogle Scholar
  59. 59.
    R. L. Smith. The Paton Prize Award. The discovery of the debrisoquine hydroxylation polymorphism: scientific and clinical impact and consequences Toxicology 168:11–19 (2001).PubMedGoogle Scholar
  60. 60.
    L. Bertilsson. Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19 Clin. Pharmacokinet. 29:192–209 (1995).PubMedCrossRefGoogle Scholar
  61. 61.
    C. Bruhn, J. Brockmoller, I. Cascorbi, I. Roots, and H. H. Borchert. Correlation between genotype and phenotype of the human arylamine N-acetyltransferase type 1 (NAT1) Biochem. Pharmacol. 58:1759–1764 (1999).PubMedGoogle Scholar
  62. 62.
    T. K. Chang, L. Yu, J. A. Goldstein, and D. J. Waxman. Identification of the polymorphically expressed CYP2C19 and the wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosphamide and ifosfamide activation Pharmacogenetics 7:211–221 (1997).PubMedGoogle Scholar
  63. 63.
    A. K. Daly, S. Cholerton, W. Gregory, and J. R. Idle. Metabolic polymorphisms Pharmacol. Ther. 57:129–160 (1993).PubMedGoogle Scholar
  64. 64.
    S. Garte, L. Gaspari, A. K. Alexandrie, C. Ambrosone, H. Autrup, J. L. Autrup, H. Baranova, L. Bathum, S. Benhamou, P. Boffetta, C. Bouchardy, K. Breskvar, J. Brockmoller, I. Cascorbi, M. L. Clapper, C. Coutelle, A. Daly, M. Dell’Omo, V. Dolzan, C. M. Dresler, A. Fryer, A. Haugen, D. W. Hein, A. Hildesheim, A. Hirvonen, L. L. Hsieh, M. Ingelman-Sundberg, I. Kalina, D. Kang, M. Kihara, C. Kiyohara, P. Kremers, P. Lazarus, L. Le Marchand, M. C. Lechner, E. M. van Lieshout, S. London, J. J. Manni, C. M. Maugard, S. Morita, V. Nazar-Stewart, K. Noda, Y. Oda, F. F. Parl, R. Pastorelli, I. Persson, W. H. Peters, A. Rannug, T. Rebbeck, A. Risch, L. Roelandt, M. Romkes, D. Ryberg, J. Salagovic, B. Schoket, J. Seidegard, P. G. Shields, E. Sim, D. Sinnet, R. C. Strange, I. Stucker, H. Sugimura, J. To-Figueras, P. Vineis, M. C. Yu, and E. Taioli. Metabolic gene polymorphism frequencies in control populations Cancer Epidemiol. Biomark. Prev. 10:1239–1248 (2001).Google Scholar
  65. 65.
    J. A. Goldsteinand and S. M. de Morais. Biochemistry and molecular biology of the human CYP2C subfamily Pharmacogenetics 4:285–299 (1994).Google Scholar
  66. 66.
    S. Hoffmeyer, O. Burk, O. von Richter, H. P. Arnold, J. Brockmoller, A. Johne, I. Cascorbi, T. Gerloff, I. Roots, M. Eichelbaum, and U. Brinkmann. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo Proc. Natl. Acad. Sci. USA 97:3473–3478 (2000).PubMedGoogle Scholar
  67. 67.
    M. Iwasaki, Y. Yoshimura, S. Asahi, K. Saito, S. Sakai, S. Morita, O. Takenaka, T. Inoda, E. Kashiyama, A. Aoyama, T. Nakabayashi, S. Omori, T. Kuwabara, T. Izumi, K. Nakamura, K. Takanaka, Y. Nakayama, M. Takeuchi, H. Nakamura, S. Kametani, Y. Terauchi, T. Hashizume, S. Nagayama, T. Kume, M. Achira, H. Kawai, T. Kawashiro, A. Nakamura, Y. Nakai, A. Kagayama, T. Shiraga, T. Niwa, T. Yoshimura, J. Morita, F. Ohsawa, M. Tani, N. Osawa, K. Ida, and K. Noguchi. Functional characterization of single nucleotide polymorphisms with amino acid substitution in CYP1A2, CYP2A6, and CYP2B6 found in the Japanese population Drug Metab. Pharmacokinet. 19:444–152 (2004).PubMedGoogle Scholar
  68. 68.
    I. Johansson, Q. Y. Yue, M. L. Dahl, M. Heim, J. Sawe, L. Bertilsson, U. A. Meyer, F. Sjoqvist, and M. Ingelman-Sundberg. Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine Eur. J. Clin. Pharmacol. 40:553–556 (1991).PubMedGoogle Scholar
  69. 69.
    U. A. Meyer and U. M. Zanger. Molecular mechanisms of genetic polymorphisms of drug metabolism Annu. Rev. Pharmacol. Toxicol. 37:269–296 (1997).PubMedGoogle Scholar
  70. 70.
    S. Ohgiya, M. Komori, H. Ohi, K. Shiramatsu, N. Shinriki, and T. Kamataki. Six-base deletion occurring in messages of human cytochrome P-450 in the CYP2C subfamily results in reduction of tolbutamide hydroxylase activity Biochem. Int. 27:1073–1081 (1992).PubMedGoogle Scholar
  71. 71.
    K. C. Ferdinand. Isosorbide dinitrate and hydralazine hydrochloride: a review of efficacy and safety Expert Rev. Cardiovasc. Ther. 3:993–1001 (2005).PubMedGoogle Scholar
  72. 72.
    S. B. Hagaand and G. S. Ginsburg. Prescribing BiDil: is it black and white? J. Am. Coll. Cardiol. 48:12–14 (2006).Google Scholar
  73. 73.
    D. M. Maraganore, M. de Andrade, T. G. Lesnick, K. J. Strain, M. J. Farrer, W. A. Rocca, P. V. Pant, K. A. Frazer, D. R. Cox, and D. G. Ballinger. High-resolution whole-genome association study of Parkinson disease Am. J. Hum. Genet. 77:685–693 (2005).PubMedGoogle Scholar
  74. 74.
    B. B. Brodie, J. Axelrod, J. R. Cooper, L. Gaudette, B. N. La Du, C. Mitoma, and S. Udenfriend. Detoxication of drugs and other foreign compounds by liver microsomes Science 121:603–604 (1955).PubMedGoogle Scholar
  75. 75.
    D. Garfinkel. Studies on pig liver microsomes. I. Enzymic and pigment composition of different microsomal fractions Arch. Biochem. Biophys. 77:493–509 (1958).PubMedGoogle Scholar
  76. 76.
    M. Klingenberg. Pigments of rat liver microsomes Arch. Biochem. Biophys. 75:376–386 (1958).PubMedGoogle Scholar
  77. 77.
    A. Y. Lu, K. W. Junk, and M. J. Coon. Resolution of the cytochrome P-450-containing omega-hydroxylation system of liver microsomes into three components J. Biol. Chem. 244:3714–3721 (1969).PubMedGoogle Scholar
  78. 78.
    D. W. Nebert and L. L. Bausserman. Genetic differences in the extent of aryl hydrocarbon hydroxylase induction in mouse fetal cell cultures J. Biol. Chem. 245:6373–6382 (1970).PubMedGoogle Scholar
  79. 79.
    A. B. Okey, G. P. Bondy, M. E. Mason, D. W. Nebert, C. J. Forster-Gibson, J. Muncan, and M. J. Dufresne. Temperature-dependent cytosol-to-nucleus translocation of the Ah receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin in continuous cell culture lines J. Biol. Chem. 255:11415–11422 (1980).PubMedGoogle Scholar
  80. 80.
    J. E. Gielen and D. W. Nebert. Aryl hydrocarbon hydroxylase induction in mammalian liver cell culture. I. Stimulation of enzyme activity in nonhepatic cells and in hepatic cells by phenobarbital, polycyclic hydrocarbons, and 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane J. Biol. Chem. 246:5189–5198 (1971).PubMedGoogle Scholar
  81. 81.
    J. Gorski and F. Gannon. Current models of steroid hormone action: a critique Annu. Rev. Physiol. 38:425–450 (1976).PubMedGoogle Scholar
  82. 82.
    T. M. Guenthner and D. W. Nebert. Cytosolic receptor for aryl hydrocarbon hydroxylase induction by polycyclic aromatic compounds. Evidence for structural and regulatory variants among established cell cultured lines J. Biol. Chem. 252:8981–8989 (1977).PubMedGoogle Scholar
  83. 83.
    A. Poland, E. Glover, and A. S. Kende. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase J. Biol. Chem. 251:4936–4946 (1976).PubMedGoogle Scholar
  84. 84.
    G. Bertilsson, J. Heidrich, K. Svensson, M. Asman, L. Jendeberg, M. Sydow-Backman, R. Ohlsson, H. Postlind, P. Blomquist, and A. Berkenstam. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction Proc. Natl. Acad. Sci. U. S. A. 95:12208–12213 (1998).PubMedGoogle Scholar
  85. 85.
    B. Blumberg, W. Sabbagh, Jr., H. Juguilon, J. Bolado, Jr., C. M. van Meter, E. S. Ong, and R. M. Evans. SXR, a novel steroid and xenobiotic-sensing nuclear receptor Genes Dev. 12:3195–3205 (1998).PubMedGoogle Scholar
  86. 86.
    S. A. Kliewer, J. T. Moore, L. Wade, J. L. Staudinger, M. A. Watson, S. A. Jones, D. D. McKee, B. B. Oliver, T. M. Willson, R. H. Zetterstrom, T. Perlmann, and J. M. Lehmann. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway Cell 92:73–82 (1998).PubMedGoogle Scholar
  87. 87.
    S. A. Kliewer, J. M. Lehmann, and T. M. Willson. Orphan nuclear receptors: shifting endocrinology into reverse Science 284:757–760 (1999).PubMedGoogle Scholar
  88. 88.
    J. J. Repa and D. J. Mangelsdorf. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis Annu. Rev. Cell Dev. Biol. 16:459–481 (2000).PubMedGoogle Scholar
  89. 89.
    T. H. Rushmore and A. N. Kong. Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes Curr. Drug Metab. 3:481–490 (2002).PubMedGoogle Scholar
  90. 90.
    J. H. Lin. Tissue distribution and pharmacodynamics: a complicated relationship Curr. Drug Metab. 7:39–65 (2006).PubMedGoogle Scholar
  91. 91.
    J. Brockmoller, J. Kirchheiner, C. Meisel, and I. Roots. Pharmacogenetic diagnostics of cytochrome P450 polymorphisms in clinical drug development and in drug treatment Pharmacogenomics 1:125–151 (2000).PubMedGoogle Scholar
  92. 92.
    M. Eichelbaum. Pharmacokinetic drug interactions. J. Clin. Pharmacol. 26:469–473 (1986).PubMedGoogle Scholar
  93. 93.
    M. T. Zuhlsdorf. Relevance of pheno- and genotyping in clinical drug development Int. J. Clin. Pharmacol. Ther. 36:607–612 (1998).PubMedGoogle Scholar
  94. 94.
    R. Weinshilboum. Inheritance and drug response N. Engl. J. Med. 348:529–537 (2003).PubMedGoogle Scholar
  95. 95.
    M. Ingelman-Sundberg. Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms Naunyn Schmiedebergs Arch. Pharmacol. 369:89–104 (2004).PubMedGoogle Scholar
  96. 96.
    W. E. Evans and M. V. Relling. Pharmacogenomics: translating functional genomics into rational therapeutics Science 286:487–491 (1999).PubMedGoogle Scholar
  97. 97.
    M. M. Shi, M. R. Bleavins, and F. A. de la Iglesia. Pharmacogenetic application in drug development and clinical trials Drug Metab. Dispos. 29:591–595 (2001).PubMedGoogle Scholar
  98. 98.
    M. W. Linder, R. A. Prough, and R. Valdes, Jr. Pharmacogenetics: a laboratory tool for optimizing therapeutic efficiency Clin. Chem. 43:254–266 (1997).PubMedGoogle Scholar
  99. 99.
    T. Friedberg, M. P. Pritchard, M. Bandera, S. P. Hanlon, D. Yao, L. A. McLaughlin, S. Ding, B. Burchell, and C. R. Wolf. Merits and limitations of recombinant models for the study of human P450-mediated drug metabolism and toxicity: an intralaboratory comparison Drug Metab. Rev. 31:523–544 (1999).PubMedGoogle Scholar
  100. 100.
    C. J. Henderson and C. R. Wolf. Transgenic analysis of human drug-metabolizing enzymes: preclinical drug development and toxicology Mol. Interv. 3:331–343 (2003).PubMedGoogle Scholar
  101. 101.
    I. S. Vizirianakis. Challenges in current drug delivery from the potential application of pharmacogenomics and personalized medicine in clinical practice Curr. Drug Deliv. 1:73–80 (2004).PubMedGoogle Scholar
  102. 102.
    C. R. Wolf. The Gerhard Zbinden memorial lecture: application of biochemical and genetic approaches to understanding pathways of chemical toxicity Toxicol. Lett. 127:3–17 (2002).PubMedGoogle Scholar
  103. 103.
    P. M. Holland, R. D. Abramson, R. Watson, and D. H. Gelfand. Detection of specific polymerase chain reaction product by utilizing the 5′–3′ exonuclease activity of Thermus aquaticus DNA polymerase Proc. Natl. Acad. Sci. U. S. A. 88:7276–7280 (1991).PubMedGoogle Scholar
  104. 104.
    P. W. Kleyn and E. S. Vesell. Genetic variation as a guide to drug development Science 281:1820–1821 (1998).PubMedGoogle Scholar
  105. 105.
    G. Luo, M. Cunningham, S. Kim, T. Burn, J. Lin, M. Sinz, G. Hamilton, C. Rizzo, S. Jolley, D. Gilbert, A. Downey, D. Mudra, R. Graham, K. Carroll, J. Xie, A. Madan, A. Parkinson, D. Christ, B. Selling, E. LeCluyse, and L. S. Gan. CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes Drug Metab. Dispos. 30:795–804 (2002).PubMedGoogle Scholar
  106. 106.
    L. G. Yengi, Q. Xiang, J. Pan, J. Scatina, J. Kao, S. E. Ball, R. Fruncillo, G. Ferron, and C. Roland Wolf. Quantitation of cytochrome P450 mRNA levels in human skin Anal. Biochem. 316:103–110 (2003).PubMedGoogle Scholar
  107. 107.
    FDA Guidance for Industry. Drug Interaction Studies—Study Design, Data Analysis, and Implications for Dosing and Labeling, 2006.Google Scholar
  108. 108.
    L. G. Yengi. Systems biology in drug safety and metabolism: integration of microarray, real-time PCR and enzyme approaches Pharmacogenomics 6:185–192 (2005).PubMedGoogle Scholar
  109. 109.
    C. Debouck and P. N. Goodfellow. DNA microarrays in drug discovery and development Nat. Genet. 21:48–50 (1999).PubMedGoogle Scholar
  110. 110.
    C. A. Harrington, C. Rosenow, and J. Retief. Monitoring gene expression using DNA microarrays Curr. Opin. Microbiol. 3:285–291 (2000).PubMedGoogle Scholar
  111. 111.
    R. J. Lipshutz, S. P. Fodor, T. R. Gingeras, and D. J. Lockhart. High density synthetic oligonucleotide arrays Nat. Genet. 21:20–24 (1999).PubMedGoogle Scholar
  112. 112.
    C. J. Henderson, D. M. Otto, D. Carrie, M. A. Magnuson, A. W. McLaren, I. Rosewell, and C. R. Wolf. Inactivation of the hepatic cytochrome P450 system by conditional deletion of hepatic cytochrome P450 reductase J. Biol. Chem. 278:13480–13486 (2003).PubMedGoogle Scholar
  113. 113.
    E. LeCluyse, A. Madan, G. Hamilton, K. Carroll, R. DeHaan, and A. Parkinson. Expression and regulation of cytochrome P450 enzymes in primary cultures of human hepatocytes J. Biochem. Mol. Toxicol. 14:177–188 (2000).PubMedGoogle Scholar
  114. 114.
    A. P. Li, S. M. Colburn, and D. J. Beck. A simplified method for the culturing of primary adult rat and human hepatocytes as multicellular spheroids In Vitro Cell Dev. Biol. 28A:673–677 (1992).PubMedGoogle Scholar
  115. 115.
    R. E. Pearce, C. J. McIntyre, A. Madan, U. Sanzgiri, A. J. Draper, P. L. Bullock, D. C. Cook, L. A. Burton, J. Latham, C. Nevins, and A. Parkinson. Effects of freezing, thawing, and storing human liver microsomes on cytochrome P450 activity Arch. Biochem. Biophys. 331:145–169 (1996).PubMedGoogle Scholar
  116. 116.
    A. P. Li, D. L. Kaminski, and A. Rasmussen. Substrates of human hepatic cytochrome P450 3A4 Toxicology 104:1–8 (1995).PubMedGoogle Scholar
  117. 117.
    J. D. Cleary, L. A. Walker, and R. L. Hawke. Antimycotic drug discovery in the age of genomics Am. J. Pharmacogenomics 5:365–386 (2005).PubMedGoogle Scholar
  118. 118.
    D. Gerhold, M. Lu, J. Xu, C. Austin, C. T. Caskey, and T. Rushmore. Monitoring expression of genes involved in drug metabolism and toxicology using DNA microarrays Physiol. Genomics. 5:161–170 (2001).PubMedGoogle Scholar
  119. 119.
    D. J. McConn and Z. Zhao. Integrating in vitro kinetic data from compounds exhibiting induction, reversible inhibition and mechanism-based inactivation: in vitro study design Curr. Drug Metab. 5:141–146 (2004).PubMedGoogle Scholar
  120. 120.
    G. Luo, J. Lin, W. D. Fiske, R. Dai, T. J. Yang, S. Kim, M. Sinz, E. LeCluyse, E. Solon, J. M. Brennan, I. H. Benedek, S. Jolley, D. Gilbert, L. Wang, F. W. Lee, and L. S. Gan. Concurrent induction and mechanism-based inactivation of CYP3A4 by an l-valinamide derivative Drug Metab. Dispos. 31:1170–1175 (2003).PubMedGoogle Scholar
  121. 121.
    Y. Konno, M. Sekimoto, K. Nemoto, and M. Degawa. Sex difference in induction of hepatic CYP2B and CYP3A subfamily enzymes by nicardipine and nifedipine in rats Toxicol. Appl. Pharmacol. 196:20–28 (2004).PubMedGoogle Scholar
  122. 122.
    D. Projean, S. Dautrey, H. K. Vu, T. Groblewski, J. L. Brazier, and J. Ducharme. Selective downregulation of hepatic cytochrome P450 expression and activity in a rat model of inflammatory pain Pharm. Res. 22:62–70 (2005).PubMedGoogle Scholar
  123. 123.
    M. P. Murphy. Current pharmacogenomic approaches to clinical drug development Pharmacogenomics 1:115–123 (2000).PubMedGoogle Scholar
  124. 124.
    B. Goodwin, E. Hodgson, and C. Liddle. The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module Mol. Pharmacol. 56:1329–1339 (1999).PubMedGoogle Scholar
  125. 125.
    N. Mizuno, T. Niwa, Y. Yotsumoto, and Y. Sugiyama. Impact of drug transporter studies on drug discovery and development Pharmacol. Rev. 55:425–461 (2003).PubMedGoogle Scholar
  126. 126.
    P. M. Beringer and R. L. Slaughter. Transporters and their impact on drug disposition Ann. Pharmacother. 39:1097–1108 (2005).PubMedGoogle Scholar
  127. 127.
    K. Ito, H. Suzuki, T. Horie, and Y. Sugiyama. Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport Pharm. Res. 22:1559–1577 (2005).PubMedGoogle Scholar
  128. 128.
    J. H. Lin. Species similarities and differences in pharmacokinetics Drug Metab. Dispos. 23:1008–1021 (1995).PubMedGoogle Scholar
  129. 129.
    Y. Sai. Biochemical and molecular pharmacological aspects of transporters as determinants of drug disposition Drug Metab. Pharmacokinet. 20:91–99 (2005).PubMedGoogle Scholar
  130. 130.
    J. E. van Montfoort, B. Hagenbuch, G. M. Groothuis, H. Koepsell, P. J. Meier, and D. K. Meijer. Drug uptake systems in liver and kidney Curr. Drug Metab. 4:185–211 (2003).PubMedGoogle Scholar
  131. 131.
    A. Bodo, E. Bakos, F. Szeri, A. Varadi, and B. Sarkadi. The role of multidrug transporters in drug availability, metabolism and toxicity Toxicol. Lett. 140–141:133–143 (2003).PubMedGoogle Scholar
  132. 132.
    K. M. Mahar Doan, J. E. Humphreys, L. O. Webster, S. A. Wring, L. J. Shampine, C. J. Serabjit-Singh, K. K. Adkison, and J. W. Polli. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs J. Pharmacol. Exp. Ther. 303:1029–1037 (2002).PubMedGoogle Scholar
  133. 133.
    G. K. Dresser, D. G. Bailey, B. F. Leake, U. I. Schwarz, P. A. Dawson, D. J. Freeman, and R. B. Kim. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine Clin. Pharmacol. Ther. 71:11–20 (2002).PubMedGoogle Scholar
  134. 134.
    M. Cvetkovic, B. Leake, M. F. Fromm, G. R. Wilkinson, and R. B. Kim. OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine Drug Metab. Dispos. 27:866–871 (1999).PubMedGoogle Scholar
  135. 135.
    M. Masuda, Y. I’Izuka, M. Yamazaki, R. Nishigaki, Y. Kato, K. Ni’inuma, H. Suzuki, and Y. Sugiyama. Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats Cancer Res. 57:3506–3510 (1997).PubMedGoogle Scholar
  136. 136.
    S. Seitz and U. A. Boelsterli. Diclofenac acyl glucuronide, a major biliary metabolite, is directly involved in small intestinal injury in rats Gastroenterology 115:1476–1482 (1998).PubMedGoogle Scholar
  137. 137.
    B. Stieger, K. Fattinger, J. Madon, G. A. Kullak-Ublick, and P. J. Meier. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver Gastroenterology 118:422–430 (2000).PubMedGoogle Scholar
  138. 138.
    C. Funk, M. Pantze, L. Jehle, C. Ponelle, G. Scheuermann, M. Lazendic, and R. Gasser. Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate Toxicology 167:83–98 (2001).PubMedGoogle Scholar
  139. 139.
    T. Korjamo, P. Honkakoski, M. R. Toppinen, S. Niva, M. Reinisalo, J. J. Palmgren, and J. Monkkonen. Absorption properties and P-glycoprotein activity of modified Caco-2 cell lines. Eur. J. Pharm. Sci. 26:266–279 (2005).PubMedGoogle Scholar
  140. 140.
    J. W. Polli, S. A. Wring, J. E. Humphreys, L. Huang, J. B. Morgan, L. O. Webster, and C. S. Serabjit-Singh. Rational use of in vitro P-glycoprotein assays in drug discovery J. Pharmacol. Exp. Ther. 299:620–628 (2001).PubMedGoogle Scholar
  141. 141.
    P. P. Annaert and K. L. Brouwer. Assessment of drug interactions in hepatobiliary transport using rhodamine 123 in sandwich-cultured rat hepatocytes Drug Metab. Dispos. 33:388–394 (2005).PubMedGoogle Scholar
  142. 142.
    P. P. Annaert, R. Z. Turncliff, C. L. Booth, D. R. Thakker, and K. L. Brouwer. P-glycoprotein-mediated in vitro biliary excretion in sandwich-cultured rat hepatocytes Drug Metab. Dispos. 29:1277–1283 (2001).PubMedGoogle Scholar
  143. 143.
    W. Lee, H. Glaeser, L. H. Smith, R. L. Roberts, G. W. Moeckel, G. Gervasini, B. F. Leake, and R. B. Kim. Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry J. Biol. Chem. 280:9610–9617 (2005).PubMedGoogle Scholar
  144. 144.
    M. Sasaki, H. Suzuki, J. Aoki, K. Ito, P. J. Meier, and Y. Sugiyama. Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein 2 Mol. Pharmacol. 66:450–459 (2004).PubMedGoogle Scholar
  145. 145.
    H. Ishizuka, K. Konno, T. Shiina, H. Naganuma, K. Nishimura, K. Ito, H. Suzuki, and Y. Sugiyama. Species differences in the transport activity for organic anions across the bile canalicular membrane J. Pharmacol. Exp. Ther. 290:1324–1330 (1999).PubMedGoogle Scholar
  146. 146.
    A. D. Shilling, F. Azam, J. Kao, and L. Leung. Use of canalicular membrane vesicles (CMVs) from rats, dogs, monkeys and humans to assess drug transport across the canalicular membrane J. Pharmacol. Toxicol. Methods 53:186–197 (2006).PubMedGoogle Scholar
  147. 147.
    J. A. Williams, R. Hyland, B. C. Jones, D. A. Smith, S. Hurst, T. C. Goosen, V. Peterkin, J. R. Koup, and S. E. Ball. Drug–drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios Drug Metab. Dispos. 32:1201–1208 (2004).PubMedGoogle Scholar
  148. 148.
    J. B. Houston and D. J. Carlile. Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices Drug Metab. Rev. 29:891–922 (1997).PubMedGoogle Scholar
  149. 149.
    H. M. Jones and J. B. Houston. Substrate depletion approach for determining in vitro metabolic clearance: time dependencies in hepatocyte and microsomal incubations Drug Metab. Dispos. 32:973–982 (2004).PubMedGoogle Scholar
  150. 150.
    R. S. Obach. 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. 27:1350–1359 (1999).PubMedGoogle Scholar
  151. 151.
    S. X. Zhao, D. Forman, N. Wallace, B. J. Smith, D. Meyer, D. Kazolias, F. Gao, J. Soglia, M. Cole, and D. Nettleton. Simple strategies for reducing sample loads in in vitro metabolic stability high-throughput screening experiments: a comparison between traditional, two-time-point and pooled sample analyses J. Pharm. Sci. 94:38–45 (2005).PubMedGoogle Scholar
  152. 152.
    Y. Naritomi, S. Terashita, A. Kagayama, and Y. Sugiyama. Utility of hepatocytes in predicting drug metabolism: comparison of hepatic intrinsic clearance in rats and humans in vivo and in vitro Drug Metab. Dispos. 31:580–588 (2003).PubMedGoogle Scholar
  153. 153.
    R. J. Riley, D. F. McGinnity, and R. P. Austin. A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes Drug Metab. Dispos. 33:1304–1311 (2005).PubMedGoogle Scholar
  154. 154.
    Y. Shibata, H. Takahashi, M. Chiba, and Y. Ishii. Prediction of hepatic clearance and availability by cryopreserved human hepatocytes: an application of serum incubation method Drug Metab. Dispos. 30:892–896 (2002).PubMedGoogle Scholar
  155. 155.
    L. P. Delbressine, C. W. Funke, M. van Tilborg, and F. M. Kaspersen. On the formation of carbamate glucuronides Xenobiotica 20:133–134 (1990).PubMedCrossRefGoogle Scholar
  156. 156.
    S. D. Hall, K. E. Thummel, P. B. Watkins, K. S. Lown, L. Z. Benet, M. F. Paine, R. R. Mayo, D. K. Turgeon, D. G. Bailey, R. J. Fontana, and S. A. Wrighton. Molecular and physical mechanisms of first-pass extraction Drug Metab. Dispos. 27:161–166 (1999).PubMedGoogle Scholar
  157. 157.
    M. F. Paine, H. L. Hart, S. S. Ludington, R. L. Haining, A. E. Rettie, and D. C. Zeldin. The human intestinal cytochrome P450 “pie” Drug Metab. Dispos. 34:880–886 (2006).PubMedGoogle Scholar
  158. 158.
    C. Y. Wu and L. Z. Benet. Predicting drug disposition via application of BCS: transport/absorption/ elimination interplay and development of a biopharmaceutics drug disposition classification system Pharm. Res. 22:11–23 (2005).PubMedGoogle Scholar
  159. 159.
    C. L. Cummins, W. Jacobsen, U. Christians, and L. Z. Benet. CYP3A4-transfected Caco-2 cells as a tool for understanding biochemical absorption barriers: studies with sirolimus and midazolam J. Pharmacol. Exp. Ther. 308:143–155 (2004).PubMedGoogle Scholar
  160. 160.
    M. F. Paine, L. Y. Leung, H. K. Lim, K. Liao, A. Oganesian, M. Y. Zhang, K. E. Thummel, and P. B. Watkins. Identification of a novel route of extraction of sirolimus in human small intestine: roles of metabolism and secretion J. Pharmacol. Exp. Ther. 301:174–186 (2002).PubMedGoogle Scholar
  161. 161.
    L. Y. Leung, H. K. Lim, M. W. Abell, and J. J. Zimmerman. Pharmacokinetics and metabolic disposition of sirolimus in healthy male volunteers after a single oral dose Ther. Drug Monit. 28:51–61 (2006).PubMedGoogle Scholar
  162. 162.
    R. L. Woosley, Y. Chen, J. P. Freiman, and R. A. Gillis. Mechanism of the cardiotoxic actions of terfenadine JAMA 269:1532–1536 (1993).PubMedGoogle Scholar
  163. 163.
    A. Markham and A. J. Wagstaff. Fexofenadine Drugs 55:269–274; (discussion 275–276) (1998).PubMedGoogle Scholar
  164. 164.
    P. Lu, M. L. Schrag, D. E. Slaughter, C. E. Raab, M. Shou, and A. D. Rodrigues. Mechanism-based inhibition of human liver microsomal cytochrome P450 1A2 by zileuton, a 5-lipoxygenase inhibitor Drug Metab. Dispos. 31:1352–1360 (2003).PubMedGoogle Scholar
  165. 165.
    T. M. Polasek, D. J. Elliot, B. C. Lewis, and J. O. Miners. Mechanism-based inactivation of human cytochrome P4502C8 by drugs in vitro J. Pharmacol. Exp. Ther. 311:996–1007 (2004).PubMedGoogle Scholar
  166. 166.
    Z. Y. Zhang and Y. N. Wong. Enzyme kinetics for clinically relevant CYP inhibition Curr. Drug Metab. 6:241–257 (2005).PubMedGoogle Scholar
  167. 167.
    T. D. Bjornsson, J. T. Callaghan, H. J. Einolf, V. Fischer, L. Gan, S. Grimm, J. Kao, S. P. King, G. Miwa, L. Ni, G. Kumar, J. McLeod, R. S. Obach, S. Roberts, A. Roe, A. Shah, F. Snikeris, J. T. Sullivan, D. Tweedie, J. M. Vega, J. Walsh, and S. A. Wrighton. The conduct of in vitro and in vivo drug–drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective Drug Metab. Dispos. 31:815–832 (2003).PubMedGoogle Scholar
  168. 168.
    W. Tang, R. W. Wang, and A. Y. Lu. Utility of recombinant cytochrome p450 enzymes: a drug metabolism perspective Curr. Drug Metab. 6:503–517 (2005).PubMedGoogle Scholar
  169. 169.
    A. L. Blobaum. Mechanism-based inactivation and reversibility: is there a new trend in the inactivation of cytochrome p450 enzymes? Drug Metab. Dispos. 34:1–7 (2006).PubMedGoogle Scholar
  170. 170.
    E. A. Dierks, K. R. Stams, H. K. Lim, G. Cornelius, H. Zhang, and S. E. Ball. A method for the simultaneous evaluation of the activities of seven major human drug-metabolizing cytochrome P450s using an in vitro cocktail of probe substrates and fast gradient liquid chromatography tandem mass spectrometry Drug Metab. Dispos. 29:23–29 (2001).PubMedGoogle Scholar
  171. 171.
    K. Ito, D. Hallifax, R. S. Obach, and J. B. Houston. Impact of parallel pathways of drug elimination and multiple cytochrome P450 involvement on drug–drug interactions: CYP2D6 paradigm Drug Metab. Dispos. 33:837–844 (2005).PubMedGoogle Scholar
  172. 172.
    B. S. Mayhew, D. R. Jones, and S. D. Hall. An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation Drug Metab. Dispos. 28:1031–1037 (2000).PubMedGoogle Scholar
  173. 173.
    J. P. O’Donnell, D. K. Dalvie, A. S. Kalgutkar, and R. S. Obach. Mechanism-based inactivation of human recombinant P450 2C9 by the nonsteroidal anti-inflammatory drug suprofen Drug Metab. Dispos. 31:1369–1377 (2003).PubMedGoogle Scholar
  174. 174.
    Y. H. Wang, D. R. Jones, and S. D. Hall. Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites Drug Metab. Dispos. 32:259–266 (2004).PubMedGoogle Scholar
  175. 175.
    J. Yang, M. Jamei, K. R. Yeo, G. T. Tucker, and A. Rostami-Hodjegan. Kinetic values for mechanism-based enzyme inhibition: assessing the bias introduced by the conventional experimental protocol Eur. J. Pharm. Sci. 26:334–340 (2005).PubMedGoogle Scholar
  176. 176.
    N. Greene, P. N. Judson, J. J. Langowski, and C. A. Marchant. Knowledge-based expert systems for toxicity and metabolism prediction: DEREK, StAR and METEOR SAR QSAR Environ. Res. 10:299–314 (1999).PubMedGoogle Scholar
  177. 177.
    H. K. Lim, N. Duczak, Jr., L. Brougham, M. Elliot, K. Patel, and K. Chan. Automated screening with confirmation of mechanism-based inactivation of CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2 in pooled human liver microsomes Drug Metab. Dispos. 33:1211–1219 (2005).PubMedGoogle Scholar
  178. 178.
    K. M. Bertelsen, K. Venkatakrishnan, L. L. Von Moltke, R. S. Obach, and D. J. Greenblatt. Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine Drug Metab. Dispos. 31:289–293 (2003).PubMedGoogle Scholar
  179. 179.
    A. Hemeryck and F. M. Belpaire. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug–drug interactions: an update Curr. Drug Metab. 3:13–37 (2002).PubMedGoogle Scholar
  180. 180.
    K. Venkatakrishnan and R. S. Obach. In vitro–in vivo extrapolation of CYP2D6 inactivation by paroxetine: prediction of nonstationary pharmacokinetics and drug interaction magnitude Drug Metab. Dispos. 33:845–852 (2005).PubMedGoogle Scholar
  181. 181.
    T. Prueksaritanont, B. Ma, C. Tang, Y. Meng, C. Assang, P. Lu, P. J. Reider, J. H. Lin, and T. A. Baillie. Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations Br. J. Clin. Pharmacol. 47:291–298 (1999).PubMedGoogle Scholar
  182. 182.
    C. Wandel, R. B. Kim, F. P. Guengerich, and A. J. Wood. Mibefradil is a P-glycoprotein substrate and a potent inhibitor of both P-glycoprotein and CYP3A in vitro. Drug Metab Dispos 28: 895–898 (2000).PubMedGoogle Scholar
  183. 183.
    F. de Longueville, F. A. Atienzar, L. Marcq, S. Dufrane, S. Evrard, L. Wouters, F. Leroux, V. Bertholet, B. Gerin, R. Whomsley, T. Arnould, J. Remacle, and M. Canning. Use of a low-density microarray for studying gene expression patterns induced by hepatotoxicants on primary cultures of rat hepatocytes Toxicol. Sci. 75:378–392 (2003).PubMedGoogle Scholar
  184. 184.
    M. R. Fielden and T. R. Zacharewski. Challenges and limitations of gene expression profiling in mechanistic and predictive toxicology Toxicol. Sci. 60:6–10 (2001).PubMedGoogle Scholar
  185. 185.
    T. Storck, M. C. von Brevern, C. K. Behrens, J. Scheel, and A. Bach. Transcriptomics in predictive toxicology Curr. Opin. Drug Discov. Dev. 5:90–97 (2002).Google Scholar
  186. 186.
    F. Boess, M. Kamber, S. Romer, R. Gasser, D. Muller, S. Albertini, and L. Suter. Gene expression in two hepatic cell lines, cultured primary hepatocytes, and liver slices compared to the in vivo liver gene expression in rats: possible implications for toxicogenomics use of in vitro systems Toxicol. Sci. 73:386–402 (2003).PubMedGoogle Scholar
  187. 187.
    J. F. Waring, G. Cavet, R. A. Jolly, J. McDowell, H. Dai, R. Ciurlionis, C. Zhang, R. Stoughton, P. Lum, A. Ferguson, C. J. Roberts, and R. G. Ulrich. Development of a DNA microarray for toxicology based on hepatotoxin-regulated sequences EHP Toxicogenomics 111:53–60 (2003).PubMedGoogle Scholar
  188. 188.
    R. A. Roth, J. P. Luyendyk, J. F. Maddox, and P. E. Ganey. Inflammation and drug idiosyncrasy-is there a connection? J. Pharmacol. Exp. Ther. 307:1–8 (2003).PubMedGoogle Scholar
  189. 189.
    D. P. Williams, N. R. Kitteringham, D. J. Naisbitt, M. Pirmohamed, D. A. Smith, and B. K. Park. Are chemically reactive metabolites responsible for adverse reactions to drugs? Curr. Drug Metab. 3:351–366 (2002).PubMedGoogle Scholar
  190. 190.
    D. C. Liebler and F. P. Guengerich. Elucidating mechanisms of drug-induced toxicity Nat. Rev. Drug Discov. 4:410–420 (2005).PubMedGoogle Scholar
  191. 191.
    J. Uetrecht. Screening for the potential of a drug candidate to cause idiosyncratic drug reactions Drug Discov. Today 8:832–837 (2003).PubMedGoogle Scholar
  192. 192.
    C. Chen, J. L. Staudinger, and C. D. Klaassen. Nuclear receptor, pregname X receptor, is required for induction of UDP-glucuronosyltranferases in mouse liver by pregnenolone-16 alpha-carbonitrile Drug Metab. Dispos. 31:908–915 (2003).PubMedGoogle Scholar
  193. 193.
    J. P. Nagpal, K. L. Khanduja, R. R. Sharma, S. Majumdar, R. Singh, M. P. Gupta, and S. C. Dogra. The effect of medroxyprogesterone acetate on the hepatic drug-metabolizing enzymes in normal and protein-deficient female rats Biochem. Med. 34:11–16 (1985).PubMedGoogle Scholar
  194. 194.
    H. U. Saarni. Time course of hepatic changes produced by medroxyprogesterone acetate in the rat Gen. Pharmacol. 17:25–29 (1986).PubMedGoogle Scholar
  195. 195.
    L. G. Yengi, Q. Xiang, L. Shen, C. Appavu, J. Kao, and J. Scatina. Application of pharmacogenomics in drug discovery and development: correlations between transcriptional modulation and preclinical safety observation. Drug metab. Lett 1:(2007).Google Scholar
  196. 196.
    I. Kola and J. Landis. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3:711–715 (2004).PubMedGoogle Scholar
  197. 197.
    M. P. Murphy, M. Bickel, D. Birkett, B. Clement, R. W. Estabrook, J. Gorrod, J. Hinson, P. Kissinger, T. Kunze, P. Maurel, P. Van Bladeren, and C. R. Wolf. History of Xenobiotic Metabolism.

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Drug Metabolism Division, Drug Safety and MetabolismWyeth ResearchCollegevilleUSA

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