Drug Metabolism: Significance and Challenges

Nuclear Receptors in Drug Metabolism

Volumn , Issue , 2008, Pages 1-41

  Prakash, Chandra ^a   Vaz, Alfin D N ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

Drug metabolism significance and challenges; Drug metabolism challenges; Phase I drug metabolizing enzymes

Indexed keywords

EID: 84890779944     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9780470409107.ch1     Document Type: Chapter

References (213)

1. Grabowski, H., Vernon, J., and DiMasi, J. (2002) Returns on research and development for 1990 drug introductions. Pharmacoeconomics 20, 11-29.
2. Caldwell, J. (2096) The role of drug metabolism studies for efficient drug discovery and development: opportunities to enhance time- and cost-efficiency. J. Pharm. Sci. 2, 117-119.
3. DiMasi, J. A., Hansen, R.W., and Grabowski, H. G. (2003) The price of innovation: new estimates of drug development costs. J. Health Econ. 22, 151-185.
4. Alavijeh, M. S. and Palmer, A. M. (2004) The pivotal role of drug metabolism and pharmacokinetics in the discovery and development of new medicines. Invest. Drugs 7, 755-763.
5. Segall, M. D., Beresford, A. P., Gola, J. M. R., Hawksley, D., and Tarbit, M. H. (2006) Focus on success: using a probabilistic approach to achieve an optimal balance of compound properties in drug discovery. Expert Opin. Drug Metab. Toxicol. 2 (2), 325-337.
6. Kola, I. and Landis, J. (2004) Can the pharmaceutical industry reduce attrition rats? Nat. Rev. Drug Discov. 3, 711-715.
7. Baranczewski, P., Stanczak, A., Kautianinen, A., Sandin, P., and Edlund, P.-O. (2006) Introduction to early in vitro identification of metabolites of new chemical entities in drug discovery and development. Pharmacol. Rep. 58, 341-352.
8. Bachmann, K. A. and Ghosh, R. (2001) The use of in vitro methods to predict in vivo pharmacokinetics and drug interactions. Curr. Drug Metab. 3, 299-314.
9. Hewitt, N. J., Ǵomez Lech́on, M. J., Houston, B. J., Hallifax, D., Brown, H. S., Maurel, P., Kenna, J. G., Gustavsson, L., Lohmann, C., Skonberg, 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 inmetabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab. Rev. 39, 159-234.
10. Beresford, A. P., Segall, M. D., and Tarbit, M. H. (2004) In silico prediction of ADME properties: are we making progress? Curr. Opin. Drug Discov. Dev. 7, 36-42.
11. Noller, J., Schmitt, J., Hartmann, T., and Loffler, T. (2005) Just married-in vitro assays and in silico ADME prediction. Screening 1, 32-33.
12. Bajorath, J. (2002) Integration of virtual and high-throughput screening. Nat. Rev. Drug Discov. 1, 882-894.
13. Mahmood, I. (2098) Interspecies scaling predicting volumes, mean residence time and elimination half-life. Some considerations. J. Pharm. Pharmacol. 50, 493-499.
14. Jang, J. R., Harris, R. Z., and Lau, D. T. (2001) Pharmacokinetics and its role in small molecule drug research. Med. Res. Rev. 21, 382-396.
15. Fura, A., Shu, Y., Zhu, M., Hanson, R. L., Roongta, V., and Humphreys, W. G. (2004) Discovering drugs through biological transformation: role of pharmacologically active metabolites in drug discovery. J. Med. Chem. 47, 4339-4351.
16. Baillie, T. A. (2003) Drug Metabolizing Enzymes: Cytochrome P450 and Other Enzymes in Drug Discovery and Development, Marcel Dekker, New York, pp. 147-154.
17. Evans, D. C., Watt, A. P., Nicoll-Griffith, D. A., and Baillie, T. (2004) Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem. Res. Toxicol. 17, 3-6.
18. Kalgutkar, A. S., Gardner, I., Obach, R. S., Shaffer, C. L., Callegari, E., Henne, K. R., Mutlib, A. E., Dalvie, D. K., Lee, J. S., Nakai, Y., et al. (2005) A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metab. 6, 161-225.
19. Clark, S. E. and Jones, B. C. (2002) Human cytochrome P450 and their role in metabolismbased drug-drug interactions. In: Drug and Pharmaceutical Sciences: Drug-Drug Interactions, Rodrigues, A. D., ed., Marcel Dekker, New York, pp. 55-88.
20. Obach, R. S. (2003) Drug-drug interactions: an important negative attribute in drugs. Drug Discov. Today 39, 301-338.
21. Watt, A. P., Mortishire-Smith, R. J., Gerhard, U., and Thomas, T. (2003) Metabolite identification in drug discovery. Drug Discov. Dev. 6, 57-65.
22. Baillie, T. A., Cayen, M. N., Fouda, H. G., Gerson, R. J., Green, J. D., Grossman, S. J., Klunk, L. J., LeBlanc, B., Perkins, D. G., and Shipley, L. A. (2002) Drug metabolites in safety testing. Toxicol. Appl. Pharmacol. 182, 188-196.
23. Smith, D. A. and Obach, R. S. (2005) Seeing through the MIST: abundance versus percentage. Commentary on metabolites in safety testing. Drug Metab. Dispos. 33, 1409-1417.
24. Guengerich, F. P. (2003) Cytochrome P450, drugs, and diseases. Mol. Interv. 3 (4), 194-204.
25. Rendic, S. (2002) Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab. Rev. 34, 83-448.
26. Shou, M., Korzekwa, K. R., Crespi, C. L., Gonzalez, F. J., and Gelboin, H. V. (2094) The role of 12 cDNA-expressed human, rodent, and rabbit cytochrome P450 in the metabolism of benzo[a]pyrene and benzo[a]pyrene trans-7,8-dihydrodiol. Mol. Carcinog. 10 (3), 159-68.
27. Shou, M., Krausz, K.W., Gonzalez, F. J., and Gelboin, H. V. (2096) Metabolic activation of the potent carcinogen dibenzo[a,l]pyrene by human recombinant cytochrome P450, lung and liver microsomes. Carcinogenesis 17, 2429-2433.
28. Baldwin, S. J., Bloomer, J. C., Smith, G. J., Ayrton, A. D., Clarke, S. E., and Chenery, R. J. (2095) Ketoconazole and sulphaphenazole as the respective selective inhibitors of P4503A and 2C9. Xenobiotica 25, 261-270.
29. Sutter, T. R., Tang, Y. M., Hayes, C. L., Wo, Y., Jabs, E. W., Li, X., Yin, H., Cody, C.W., and Greenlee,W. F. (2094) Complete cDNA sequence of a human dioxin-inducible mRNA identifies a new gene subfamily of cytochrome P450 that maps to chromosome J. Biol. Chem. 269, 13092-13099.
30. Murray, G. I., Taylor, M. C., Mcfadyen, M. C., McKay, J. A., Greenlee, W. F., Burke, M. D., and Melvin,W. T. (2097) Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Res. 57, 3026-3031.
31. Belous, A. R., Hachey, D. L., Dawling, S., Roodi, N., and Parl, F. F. (2007) Cytochrome P 450 1B1-mediated estrogen metabolism results in estrogen-deoxyribonucleoside adduct formation. Cancer Res. 67 (2), 812-817.
32. Hukkanen, J., Pelkonen, O., Hakkola, J., and Raunio, H. (2002) Expression and regulation of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes in human lung. Crit. Rev. Toxicol. 32 (5), 391-411.
33. Nebert, D. W., Dalton, T. P., Okey, A. B., and Gonzalez, F. J. (2004) Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J. Biol. Chem. 279 (23), 23847-23850.
34. Guengerich, F. P. (2097) Comparisons of catalytic selectivity of cytochrome P450 subfamily enzymes from different species. Chem. Biol. Interact. 106 (3), 161-82.
35. Honkakoski, P. and Negish, M. (2097) The Structure, function, and regulation of cytochrome P450 2A enzymes. Drug Metab. Rev. 29, 977-996.
36. Smith, G. B. J., Bend, J. R., Bedard, J. J., Reid, K. R., Petsikas, D., and Massey, T. E. (2003) Biotransformation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in peripheral human lung microsomes. Drug Metab. Dispos. 31 (9), 1134- 1141.
37. Ruangyuttikarn, W., Appleton, M. L., and Yost, G. S. (2091) Metabolism of 3-methylindole in human tissues. Drug Metab. Dispos. 19 (5), 977-84.
38. He, X. Y., Tang, L., Wang, S. L., Cai, Q. S., Wang, J. S., and Hong, J. Y. (2006) Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract. Int. J. Cancer 118, 2665-2671.
39. Rivera, S. P., Saarikoski, S. T., and Hankinson, O. (2002) Identification of a novel dioxininducible cytochrome P450. Mol. Pharmacol. 61 (2), 255-259.
40. Court, M. H., Duan, S. X., Hesse, L. M., Venkatakrishnan, K., and Greenblatt, D. J. (2001) Cytochrome P450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Anesthesiology 94, 110-119.
41. Lang, T. A., Klein, K. A., Fischer, J. A., Nussler, A. K. B., Neuhaus, P. B., Hofmann, U. A., Eichelbaum, M. A., Schwab, M. A., and Zanger, U. M. A. (2001) Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 11, 399-415.
42. Code, E. L., Crespi, C. L., Penman, B. W., Gonzalez, F. J., Chang, T. K., and Waxman, D. J. (2097) Human cytochrome P4502B6: interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metab. Dispos. 25, 985-993.
43. Lamba, V., Lamba, J., Yasuda, K., Strom, S., Davila, J., Hancock, M. L., Fackenthal, J. D., Rogan, P.K., Ring, B., Steven, A., et al. (2003) Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J. Pharmacol. Exp. Ther. 307, 906-922.
44. Romkes, M., Faletto, M. B., Blaisdell, J. A., Raucy, J. L., and Goldstein, J. A. (2091) Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily. Biochemistry 30, 3247-3255.
45. Zuber, R., Anzenbacherova, E., and Anzenbacher, P. (2002) Cytochrome P450 and experimental models of drug metabolism. J. Cell. Mol. Med. 6, 189-198.
46. Hanioka, N., Kimura, S., Meyer, U. A., and Gonzalez, F. J. (2090) The human CYP2D6 locus associates with a common genetic defect in drug oxidation: a G1934 to a base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3_ splice recognition site. Am. J. Hum. Genet. 47, 994-1001.
47. Mulder, H., Herder, A., Wilmink, F. W., Tamminga, W. J., Belitser, S. V., and Egberts, A. C. G. (2006) The impact of cytochrome P450-2D6 genotype on the use and interpretation of therapeutic drug monitoring in long-stay patients treated with antidepressant and antipsychotic drugs in daily psychiatric practice. Pharmacoepidemiol. Drug Saf. 15 (2), 107-114.
48. Lofgren, S., Hagbjork, A., Ekman, S., Fransson-Steen, R., and Terelius, Y. (2004) Metabolism of human cytochrome P450 marker substrates in mouse: a strain and gender comparison. Xenobiotica 34, 811-834.
49. Ronis, M. J. J., Lindros, K. O., Ingelman-Sundberg, M., Ioannides, C., and Parke, D. V., eds. (2096) Cytochromes P450: Metabolic and Toxicological Aspects. 9, The CYP2E Subfamily, CRC Press, Boca Raton, FL, pp. 211-239.
50. Carr, B. A., Wan, J., Hines, R. N., and Yost, G. S. (2003) Characterization of the human lung CYP2F1 gene and identification of a novel lung-specific binding motif. J. Biol. Chem. 278 (18), 15473-15483.
51. Lanza, D. L., Code, E., Crespi, C. L., Gonzalez, F. J., and Yost, G. S. (2099) Specific dehydrogenation of 3-methylindole and epoxidation of naphthalene by recombinant human CYP2F1 expressed in lymphoblastoid cells. Drug Metab. Dispos. 27, 798-803.
52. Thornton-Manning, J., Appleton, M. L., Gonzalez, F. J., and Yost, G. S. (2096) Metabolism of 3-methylindole by vaccinia-expressed P450 enzymes: correlation of 3-methyleneindolenine formation and protein-binding. J. Pharmacol. Exp. Ther. 276 (1), 21-29.
53. Zeldin, D. C., Foley, J., Ma, J., Boyle, J. E., Pascual, J. M., Moomaw, C. R., Tomer, K. B., Steenbergen, C., and Wu, S. (2096) CYP2J subfamily P450s in the lung: expression, localization, and potential functional significance. Mol. Pharmacol. 50 (5), 1111- 1117.
54. Matsumoto, S., Hirama, T., Matsubara, T., Nagata, K., and Yamazoe, Y. (2002) Involvement of CYP2J2 on the intestinal first-passmetabolism of antihistamine drug, astemizole. Drug Metab. Dispos. 30 (11), 1240-1245.
55. Hoffman, S. M., Nelson, D. R., and Keeney, D. S. (2001) Organization, structure and evolution of the CYP2S gene cluster on human chromosome 19. Pharmacogenetics 11, 687-698.
56. Karlgren, M., Miura, S., and Ingelman-Sundberg, M. (2005) Novel extrahepatic cytochrome P450s. Toxicol. Appl. Pharmacol. 207 (2, Suppl.), S57-S61.
57. Buckpitt, A., Boland, B., Isbell, M., Morin, D., Shultz, M., Baldwin, R., Chan, K., Karlson, A., Lin, C., Taff, A., et al. (2002) Naphthalene-induced respiratory tract toxicity: metabolic mechanisms of toxicity. Drug Metab. Rev. 34 (4), 791-820.
58. Wrighton, S. A., VandenBranden, M., and Ring, B. J. (2096) The human drug metabolizing cytochrome P450. J. Pharmacokinet. Biopharmacol. 24, 461-473.
59. Li, A. P., Kaminsky, D. L., and Rasmussen, A. (2095) Substrate of human hepatic cytochrome P450 3A4. Toxicol. 104, 1-8.
60. Domanski, D. L., Finta, C., Halpert, J. R., and Zaphiropoulos, P. G. (2001) cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450. Mol. Pharmacol. 59, 386-392.
61. Williams, J. A., Ring, B. J., Cantrell, V. E., Jones, D. R., Eckstein, J., Ruterbories, K., Hamman, M. A., Hall, S. D., and Wrighton, S. A. (2002) Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab. Dispos. 30, 883-891.
62. Gellner, K., Eiselt, R., Hustert, E., Arnold, H., Koch, I., Haberl, M., Deglmann, C. J., Burk, O., Buntefuss, D., Escher, S., et al. (2001) Genomic organization of the human CYP3A locus: identification of a new inducible CYP3A gene. Pharmacogenetics 11, 111-121.
63. Nebert, D. W. and Russell, D. W. (2002) Clinical importance of the cytochromes P450. Lancet 360, 1155-1162.
64. Marill, J., Cresteil, T., Lanotte,M., and Chabot, G. G. (2000) Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites. Mol. Pharmacol. 58, 1341-1348.
65. Cashman, J. R. (2000) Human flavin-containing monooxygenase: substrate specificity and role in drug metabolism. Curr. Drug Metab. 1, 1037-1045.
66. Zhang, J. and Cashman, J. R. (2006) Quantitative analysis of FMO gene mRNA levels in human tissues. Drug Metab. Dispos. 34 (1), 19-26.
67. Shih, J. C., Chen, K., and Ridd, M. J. (2099) Monoamine oxidase from genes to behavior. Annu. Rev. Neurosci. 22, 197-217.
68. Kalgutkar, A. S., Dalvie, D. K., Castagnoli, N., Jr., and Taylor, T. J. (2001) Interactions of nitrogen-containing xenobiotics with monoamine oxidase (MAO) isozymes A and B: SAR studies on MAO substrates and inhibitors. Chem. Res. Toxicol. 14 (9), 1139-1162.
69. Rashidi, M. R., Smith, J. A., Clarke, S. E., and Beedham, C. (2097) In vitro oxidation of famciclovir and 6-deoxypenciclovir by aldehyde oxidase from human, guinea pig, rabbit, and rat liver. Drug Metab. Dispos. 25, 805-813.
70. Lake, B. G., Ball, S., Kao, J., Renwick, A. B., Price, R. J., and Scatina, J. A. (2002) Metabolism of zaleplon by human liver: evidence for involvement of aldehyde oxidase. Xenobiotica 32, 835-847.
71. Sugihara, K., Kitamura, S., and Tatsumi, K. (2096) Involvement of mammalian liver cytosols and aldehyde oxidase in reductive metabolism of zonisamide. Drug Metab. Dispos. 24, 199-202.
72. Kamel, A., Prakash, C., and Obach, S. (2002) Determination of the enzyme involved in the reductive metabolism of ziprasidone to dihydroziprasidone and the formation of S-methyl dihydroziprasidone using human in vitro systems and electrospray ionization tandem mass spectrometry. Proceedings of the 50th ASMS Conference, Orlando, USA.
73. Pristos, C. A. and Gustafson, D. L. (2094) Xanthine dehydrogenase and its role in cancer chemotherapy. Oncol. Res. 6, 477.
74. Benhamou, S., Reinikanen, M., Bouchardy, C., Dayer, P., and Hirvonen, A. (2098) Association between lung cancer and microsomal epoxide hydrolase genotypes. Cancer Res. 58, 5291-5293.
75. Razonable, R. R. and Paya, C. V. (2004) Valganciclovir for the prevention and treatment of cytomegalovirus disease in immunocompromised hosts. Expert Rev. Anti-infect. Ther. 2 (1), 27-42.
76. McClellan, K. and Perry, C. M. (2001) Oseltamivir: a review of its use in influenza. Drugs 61 (2), 261-283.
77. Tukey, R. H. and Strassburg, C. P. (2000) Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu. Rev. Pharmacol. Toxicol. 40, 581-616.
78. Evans, R. W. and Relling, M. V. (2099) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487-491.
79. Hawes, E. (2098)N+-glucuronidation, a common pathway in humanmetabolism of drugs with tertiary amine group. Drug Metab. Dispos. 26 (9), 830-837.
80. Benet, L. Z. and Spahn, H. (2088) Acyl migration and covalent binding of drug glucuronides-potential toxicity mediators. Colloq. INSERM 173, 261-269.
81. Kauffman, F. C. (2004) Sulfonation in pharmacology and toxicology. Drug Metab. Rev. 36, 823-843.
82. Hayes, J. D. and Pulford, D. J. (2095) The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit. Rev. Biochem. Mol. Biol. 30, 445-600.
83. Zhou, S., Chan, E., Duan, W., Huang, M., and Chen, Y.-Z. (2005) Drug bioactivation: covalent binding to target proteins and toxicity relevance. Drug Metab. Rev. 37 (1), 41-213.
84. Grant, D. M. (2093) Molecular genetics of N-acetyltransferases. Pharmacogenetics 3, 45-50.
85. Hanna, P. E. (2096) Metabolic activation and detoxification of arylamines. Curr. Med. Chem. 3, 195-210.
86. Tenhunen, J., Salminen, M., Lundstr̈om, K., Kiviluoto, T., Savolainen, R., and Ulmanen, I. (2094) Genomic organization of the human catechol-O-methyltransferase gene and its expression from two distinct promoters. Eur. J. Biochem. 223, 1049-1059.
87. Weinshilboum, R. M., Otterness, D. M., and Szumlanski, C. L. (2099) Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu. Rev. Pharmacol. Toxicol. 39, 19-52.
88. Prakash, C., Kamel, A., Gummerus, J., and Wilner, K. (2097) Metabolism and excretion of the antipsychotic drug, ziprasidone, in humans. Drug Metab. Dispos. 25, 863-872.
89. Pacifici, G. M., Donatelli, P., and Giuliani, L. (2092) Histamine N-methyl transferase: inhibition by drugs. Br. J. Clin. Pharmacol. 34 (4), 322-327.
90. Pahlich, S., Zakaryan, R. P., and Gehring, H. (2006) Protein arginine methylation: cellular functions and methods of analysis. Biochim. Biophys. Acta, Protein. Proteomics 1764 (12), 1890-1903.
91. Beringer, P. M. and Salughter, R. L. (2005) Transporters and their impact on drug disposition. Ann. Pharmacother. 39, 1097-1108.
92. vanMontfoort, J. E., Hagenbuch, B., Groothuis, H., Koepsell, H.,Meier, P. J., andMeijer, D. K. (2003) Drug uptake systems in liver and kidney. Curr. Drug Metab. 4, 185-211.
93. Chen, C. J.,Chin, J. E.,Ueda,K., Clark,D. P.,Pastan, I.,Gottesman,M.M., andRobinson, I. B. (2086) Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47, 381-389.
94. Ambudkar, S. V., Kimchi-sarfaty, C., Sauna, Z. E., and Gottesman, M. M. (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22, 7468-7485.
95. Marzolini, C., Paus, E., Buclin, T., and Kim, R. B. (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin. Pharmacol. Ther. 75, 13-33.
96. Deeley, R. G. and Cole, S. P. C. (2006) Substrate recognition and transport by multidrug resistance protein 1 (ABCC1). FEBS Lett. 580, 1103-1111.
97. Sandusky, G. E., Mintze, K. S., Pratt, S. E., and Dantzig, A. H. (2002) Expression of multidrug resistance-associated protein 2 (MRP2) in normal human tissues and carcinomas using tissue microarrays. Histopathology 41, 65-74.
98. Hirohashi, T., Suzuki, H., Chu, X. Y., Tamai, I., Tsuji, A., and Sugiyama, Y. (2000) Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (Caco-2). J. Pharmacol. Exp. Ther. 292, 265-270.
99. Loscher, W. and Potschka, H. (2005) Drug resistance in brain diseases and the role of drug efflux transporters. Nat. Rev. Neurosci. 6, 591-602.
100. Kartenbeck, J., Leuschner, U.,Mayer, R., and Keepler, D. (2096) Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson Syndrome. Hepatology 23, 106-066.
101. Doyle, L. A., Yang, W., Abruzzo, L. V., Krogmann, T., Gao, Y., Rishi, A. K., and Ross, D. D. (2098) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl Acad. Sci. USA 95, 15665-15670.
102. Miyake, K., Mickley, L., Litman, T., Zhan, Z., Robey, R., Cristensen, B., Brangi, M., Greenberger, L., Dean, M., Fojo, T., et al. (2099) Molecular cloning of CDNAs which are highly over expressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res. 59, 8-13.
103. Maliepaard, M., Scheffer, G. L., Faneyte, I. F., van Gastelen, M. A., Pijnenborg, A. C., Schinkel, A. H., van De Vijver, M. J., Scheper, R. J., and Schellens, J. H. (2001) Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. 61, 3458-3464.
104. Jonker, J. W., Smit, J. W. M., Brinkhuis, R. F., Maliepaard, M., Beijnen, J. H., Schellens, J. H., and Schinkel, A. H. (2000) Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J. Natl. Cancer Inst. 92, 1651-1656.
105. Ifergan, A., Shafran, G., Jansen, J., Hooijberg, H., Scheffer, G. L., and Assaraf, Y. G. (2004) Folate deprivation results in the loss of breast cancer resistance protein (BCRP/ABCG2) expression. A role for BCRP in cellular folate homeostasis. J. Biol. Chem. 279, 25527-25534.
106. Suzuki, H. and Sugiyama, Y. (2000) Transport of drugs across the hepatic sinusoidal membrane: sinusoidal drug influx and efflux in the liver. Semin. Liver Dis. 20, 251-263.
107. Hagenbuch, B. and Meier, P. J. (2003) The superfamily of organic anion transporting polypeptides. Biochim. Biophys. Acta 1, 1-18.
108. Lee, W. and Kim, R. B. (2004) Transporter and renal drug elimination. Annu. Rev. Pharmacol. Toxicol. 44, 137-166.
109. Sweet, D. H. and Pritchard, J. B. (2099) The molecular biology of renal organic anion and organic cation transporters. Cell. Biochem. Biophys. 31, 89-118.
110. De Graff, C., Vermeulen, N. P. E., and Feenstra, K. A. (2005) Cytochrome P450 in silico: an integrative modeling approach. J. Med. Chem. 48 (8), 2725-2755.
111. Ekins, S., Nikolsky, Y., Nikolskaya, T., and GeneGo, S. J. (2005) Techniques: application of systems biology to absorption, distribution, metabolism, excretion and toxicity. Trends Pharmacol. Sci. 26 (4), 202-209.
112. Afzelius, L., Arnby, C. H., Broo, A., Carlsson, L., Isaksson, C., Ulrik Jurva, U., Kjellander, B.,Kolmodin, K.,Nilsson, K., Raubacher, F., et al. (2007) State of the art tools for computational site of metabolism predictions: comparative analysis, mechanistically insights, and future applications. Drug Metab. Rev. 39, 61-86.
113. De Groot, M. J., Auckland, M. J., Horne, V. A., Alex, A. A., and Jones, B. C. (2099) A novel approach to predicting P450-mediated drug metabolism. CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6. J. Med. Chem. 42, 4062-4070.
114. Afzelius, L., Zamora, I., Masimirembwa, C. M., Karle, A., Anderson, T. B., Mecucci, S., Baroni, M., and Cruciani, G. (2004) Conformer- and alignment independent model for predicting structurally diverse competitive CYP2C9 inhibitors. J. Med. Chem. 47, 907-914.
115. Boxenbaum, H. (2084) Interspecies pharmacokinetic scaling and the evolutionarycomparative paradigm. Drug Metab. Rev. 15, 1071-1121.
116. Mahmood, I. and Balian, J. D. (2096) Interspecies scaling: prediction clearance of drugs in humans: three different approaches. Xenobiotica 26, 887-895.
117. Feng, M. R., Lou, X., Brown, R. R., and Hutchaleelaha, A. (2000) Allometric pharmacokinetic scaling: towards the prediction of human oral pharmacokinetics. Pharm. Res. 17, 410-418.
118. Nagilla, R. and Ward, K. W. (2004) A comprehensive analysis of the role of correction factors in the allometric predictivity of clearance from rat, dog, and monkey to humans. J. Pharm. Sci. 93 (10), 2522-2534.
119. Obach, R. S., Baxter, J. G., Liston, T. E., Silber, B. M., Jones, B. C.,Macintyre, F., Rance, D. J., and Wastall, P. (2097) The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J. Pharmacol. Exp. Ther. 283 (1), 46-58.
120. Lave, T., Dupin, S., Schmitt, C., Chou, R. C., Jaeck, D., and Coassolo, P. F. (2097) Integration of in vitro data into allometric scaling to predict hepatic metabolic clearance in man: application to 10 extensively metabolized drugs. J. Pharm. Sci. 86 (5), 584-590.
121. Caldwell, G.W., Masucci, J. A., Yan, Z., and Hageman,W. (2004) Allometric scaling of pharmacokinetic parameters in drug discovery: can human CL, Vss and t1/2 be predicted from in-vivo rat data? Eur. J. Drug Metab. Pharmacokinet. 29 (2), 133-143.
122. McLean, M. A., Tam, C. J., Baratta, M. T., Holliman, C. L., Ings, R. M., and Galluppi, G. R. (2007) Accelerating drug development: methodology to support first-in-man pharmacokinetic studies by the use of drug candidate microdosing. Drug Dev. Res. 68 (1), 14-22.
123. Balani, S. K., Nagaraja, N. V., Qian, M. G., Costa, A. O., Daniels, J. S., Yang, H., Shimoga, P. R., Wu, J. T., Gan, L., Lee, F. W., et al. (2006) Evaluation of microdosing to assess pharmacokinetic linearity in rats using liquid chromatography-tandem mass spectrometry. Drug Metab. Dispos. 34 (3), 384-388.
124. Lappin, G., Kuhnz, W., Jochemsen, R., Kneer, J., Chaudhary, A., Oosterhuis, B., Drijfhout, W., Rowland, M., and Garner, R. C. (2006) Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs. Clin. Pharmacol. Ther. 80 (3), 203-215.
125. Sarapa, N. (2007) Exploratory IND: a new regulatory strategy for early clinical drug development in the United States. Ernst Schering Res. Found. Workshop 59, 151-163, 116b.
126. Bertino, J. S., Jr., Greenberg, H. E., and Reed,M. D. (2007) American College of Clinical Pharmacology position statement on the use of microdosing in the drug development process. J. Clin. Pharmacol. 47 (4), 418-422.
127. Prakash, C., Shaffer, C., Tremaine, L., Liberman, R., Skipper, P., Flarakos, J., and Tannenbaum, S. (2007) Application of liquid chromatography-accelerator mass spectrometry (LC-AMS) to evaluate the metabolic profiles of a drug candidate in human urine and plasma. Drug Metab. Lett., 1 (3), 226-231.
128. Souhaili, E. A.,Batt, A. M., and Siest, G. (2086) Comparison of cytochrome P-450 content and activities in liver microsomes of seven animal species, including man. Xenobiotica 16 (4), 351-358.
129. Labedzki, A., Buters, J., Jabrane, W., and Fuhr, U. (2002) Differences in caffeine and paraxanthine metabolism between human and murine CYP1A2. Biochem. Pharmacol. 63 (12), 2159-2167.
130. Bjornsson, T. D., Callaghan, J. T., Einolf, H. J., Fischer, V., Gan, L., Grimm, S., Kao, J., King, S. P., Miwa, G., Ni, L., et al. (2003) The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J. Clin. Pharmacol. 43, 443-469.
131. Wienkers, L. C. and Heath, H. G. (2005) Risk assessment for drug-drug interactions caused by metabolism-based inhibition of CYP3A4 using automated in vitro assay systems and its application in early discovery process. Drug Metab. Dispos. 35 (7), 1232-1238.
132. Vickers, A. E. M., Sinclair, J. R., Zollinger, M., Heitz, F., Glanzel, U., Johanson, L., and Fischer, V. (2099) Multiple cytochrome P-450s involved in the metabolism of terbinafine suggest a limited potential for drug-drug interactions. Drug Metab. Dispos. 27 (9), 1029-1038.
133. Elewski, B. and Tavakkol, A. (2005) Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality. Ther. Clin. Risk Manag. 1 (4), 299-306.
134. Gibbs, J. P., Hyland, R., and Youdim, K. (2006) Minimizing polymorphic metabolism in drug discovery: evaluation of the utility of in vitro methods for predicting pharmacokinetic consequences associated with CYP2D6 metabolism. Drug Metab. Dispos. 34, 1516-1522.
135. Honig, P. K.,Wortham,D.C., Zamani,K., Conner, D. P.,Mullin, J.C., andCantilena, L.R. (2093) Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. J. Am. Med. Assoc. 269 (12), 1513-1518.
136. Guengerich, F. P. and Kim, D. H. (2090) In vitro inhibition of dihydropyridine oxidation and aflatoxinB1 activation in human liver microsomes by naringenin and other flavonoids. Carcinogenesis 11 (12), 2275-2279.
137. Hollander, A. A., van Rooij, J., Lentjes, G.W., Arbouw, F., van Bree, J. B., Schoemaker, R. C., van Es, L. A., Van Der Woude, F. J., and Cohen, A. F. (2095) The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. Clin. Pharmacol. Ther. 57 (3), 318-324.
138. Bailey, D. G., Malcolm, J., Arnold, O., and Spence, J. D. (2098) Grapefruit juice-drug interactions. Br. J. Clin. Pharmacol. 46 (2), 101-110.
139. Greenblatt, D. J., von Moltke, L. L., Harmatz, J. S., Chen, G., Weemhoff, J. L., Jen, C., Kelley, C. J., LeDuc, B. W., and Zinny, M. A. (2003) Time course of recovery of cytochrome P450 3A function after single doses of grapefruit juice. Clin. Pharmacol. Ther. 74 (2), 121-129.
140. Hidaka, M., Okumura, M., Fujita, K., Ogikubo, T., Yamasaki, K., Iwakiri, T., Setoguchi, N., and Arimori, K. (2005) Effects of pomegranate juice on human cytochrome P450 3A (CYP3A) and carbamazepine pharmacokinetics in rats. Drug Metab. Dispos. 33 (5), 644-648.
141. Egashira,K., Ohtani,H., Itoh, S.,Koyabu, N., Tsujimoto, M.,Murakami, H., and Sawada, Y. (2004) Inhibitory effects of pomelo on the metabolism of tacrolimus and the activities of CYP3A4 and P-glycoprotein. Drug Metab. Dispos. 32 (8), 828-833.
142. Harris, R. Z., Jang, G. R., and Tsunoda, S. (2003) Dietary effects on drug metabolism and transport. Clin. Pharmacokinet. 42 (13), 1071-1088.
143. Guo, L., Taniguchi, M., Xiao, Y., Baba, K., Ohta, T., and Yamazoe, Y. (2000) Inhibitory effect of natural furanocoumarins on human microsomal cytochrome P450 3A activity. Japan. J. Pharmacol. 82 (2), 122-129.
144. Venkatakrishnan, K., von Moltke, L. L., and Greenblatt, D. J. (2098) Relative quantities of catalytically active CYP 2C9 and 2C19 in human liver microsomes: application of the relative activity factor approach. J. Pharm. Sci. 87 (7), 845-853.
145. Gelboin, H. V., Krausz, K. W., Gonzalez, F. J., and Yang, T. J. (2099) Inhibitory monoclonal antibodies to human cytochrome P450 enzymes: a new avenue for drug discovery. Trends Pharmacol. Sci. 20 (11), 432-438.
146. Lu, A. Y. H., Wang, R. W., and Lin, J. H. (2003) Cytochrome P450 in vitro reaction phenotyping: a re-evaluation of approaches used for P450 isoform identification. Drug Metab. Dispos. 31 (4), 345-350.
147. Rodrigues, D. (2099) Integrated cytochrome P450 reaction phenotyping: attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes. Biochem. Pharmacol. 57 (5), 465-480.
148. Venkatakrishnan, K., von Moltke, L. L., and Greenblatt, D. J. (2001) Human drug metabolism and the cytochromes P450: application and relevance of in vitro models. J. Clin. Pharmacol. 41 (11), 1149-1179.
149. Trapnell, C. B., Klecker, R. W., Jamis-Dow, C., and Collins, J. M. (2098) Glucuronidation of 3_-azido-3_-deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. Antimicrob. Agents Chemother. 42 (7), 1592-1596.
150. Bernard, O., Tojcic, J., Journault, K., Perusse, L., and Guillemette, C. (2006) Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid. Drug Metab. Dispos. 34 (9), 1539-1545.
151. Borlak, J., Gasparic, A., Locher, M., Schupke, H., and Hermann, R. (2006) NGlucuronidation of the antiepileptic drug retigabine: results from studies with human volunteers, heterologously expressed human UGTs, human liver, kidney, and liver microsomal membranes of Crigler-Najjar type II. Metab. Clin. Exp. 55 (6), 711-721.
152. Yu, L., Lu, S., Lin, Y., and Zeng, S. (2007) Carboxyl-glucuronidation of mitiglinide by human UDP-glucuronosyltransferases. Biochem. Pharmacol. 73 (11), 1842-1851.
153. Gaganis, P., Miners, J. O., and Knights, K. M. (2007) Glucuronidation of fenamates: kinetic studies using human kidney cortical microsomes and recombinant UDPglucuronosyltransferase (UGT) 1A9 and 2B7. Biochem. Pharmacol. 73 (10), 1683- 1691.
154. Bauman, J. N., Goosen, T. C., Tugnait, M., Peterkin, V., Hurst, S. I., Menning, L. C., Milad, M., Court, M. H., andWilliams, J. A. (2005) UDP-glucuronosyltransferase 2B7 is themajor enzyme responsible for gemcabene glucuronidation in human liver microsomes. Drug Metab. Dispos. 33 (9), 1349-1354.
155. Kehrer, D. F. S., Mathijssen, R. H. J., Verweij, J., de Bruijn, P., and Sparreboom, A. (2002) Modulation of irinotecan metabolism by ketoconazole. J. Clin. Oncol. 20 (14), 3122-3129.
156. Federman, D. G., Hussain, F., andWalters, A. B. (2001) Fatal rhabdomyolysis caused by lipid-lowering therapy. South. Med. J. 94 (10), 1023-1026.
157. Prueksaritanont, T., Zhao, J. J., Ma, B., Roadcap, B. A., Tang, C., Qiu, Y., Liu, L., Lin, J. H., Pearson, P. G., and Baillie, T. A. (2002) Mechanistic studies on metabolic interactions between gemfibrozil and statins. J. Pharmacol. Exp. Ther. 301 (3), 1042-1051.
158. Prueksaritanont, T., Qiu, Y., Mu, L., Michel, K., Brunner, J., Richards, K. M., and Lin, J. H. (2005) Interconversion pharmacokinetics of simvastatin and its hydroxy acid in dogs: effects of gemfibrozil. Pharm. Res. 22 (7), 1101-1109.
159. Beedham, C., Critchley, D. J. P., and Rance, D. J. (2095) Substrate specificity of human liver aldehyde oxidase toward substituted quinazolines and phthalazines: a comparison with hepatic enzyme from guinea pig, rabbit, and baboon. Arch. Biochem. Biophys. 319 (2), 481-490.
160. Rashidi, M. R., Smith, J. A., Clarke, S. E., and Beedham, C. (2097) In vitro oxidation of famciclovir and 6-deoxypenciclovir by aldehyde oxidase from human, guinea pig, rabbit, and rat liver. Drug Metab. Dispos. 25 (7), 805-813.
161. Schofield, P. C., Robertson, I. G., and Paxton, J. W. (2000) Inter-species variation in the metabolism and inhibition of N-[(2__-dimethylamino)ethyl]acridine-4-carboxamide (DACA) by aldehyde oxidase. Biochem. Pharmacol. 59 (2), 161-165.
162. Obach, R. S. (2004) Potent inhibition of human liver aldehyde oxidase by raloxifene. Drug Metab. Dispos. 32 (1), 89-97.
163. Xia, C. Q., Milton, M. N., and Gan, L.-S. (2007) Evaluation of drug-transporter interactions using in vitro and in vivo models. Curr. Drug Metab. 8, 341-363.
164. Li, J. H. (2007). Transporter-mediated drug interactions: clinical implications and in vitro assessment. Expert Opin. Drug Metab. Toxicol. 3 (1), 81-92.
165. Kalgutkar, A. S., Obach, R. S., and Maurer, T. S. (2007) Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions. Curr. Drug Metab. 8 (5), 407-447.
166. Mutlib, A., Lam, W., Atherton, J., Chen, H., Galatsis, P., and Stolle, W. (2005) Application of stable isotope labeled glutathione and rapid scanning mass spectrometers in detecting and characterizing reactive metabolites. Rapid Commun. Mass Spectrom. 19 (23), 3482-3492.
167. Argoti, D., Liang, L., Conteh, A., Chen, L., Bershas, D., Yu, C., Vouros, P., and Yang, E. (2005) Cyanide trapping of iminium ion reactive intermediates followed by detection and structure identification using liquid chromatography-tandemmass spectrometry (LCMS/ MS). Chem. Res. Toxicol. 18 (10), 1537-1544.
168. Castro-Perez, J., Plumb, R., Liang, L., and Yang, E. (2005) A high-throughput liquid chromatography/tandem mass spectrometry method for screening glutathione conjugates using exact mass neutral loss acquisition. Rapid Commun. Mass Spectrom. 19 (6), 798-804.
169. Yan, Z., Maher, N., Torres, R., and Huebert, N. (2007) Use of a trapping agent for simultaneous capturing and high-throughput screening of both "soft" and "hard" reactive metabolites. Anal. Chem. 79 (11), 4206-4214.
170. Zheng, J.,Ma, L.,Xin, B., Olah, T., Humphreys, G.W., and Zhu, M. (2007) Screening and identification of GSH-trapped reactive metabolites using hybrid triple quadruple linear ion trap mass spectrometry. Chem. Res. Toxicol. 20 (5), 757-766.
171. Doss, G. A. and Baillie, T. A. (2006) Addressing metabolic activation as an integral component of drug design. Drug Metab. Rev. 38 (4), 641-649.
172. Kroemer, H. K. and Klotz, U. (2092) Glucuronidation of drugs. A re-evaluation of the pharmacological significance of the conjugates and modulating factors. Clin. Pharmacokinet. 23, 292-310.
173. Boelsterli, U. A., Zimmerman, H. J., and Kretz-Rommel, A. (2095) Idiosyncratic liver toxicity of nonsteroidal anti-inflammatory drugs: molecular mechanisms and pathology. Crit. Rev. Toxicol. 25 (3), 207-235.
174. Bailey, M. J. and Dickinson, R. G. (2003) Acyl glucuronide reactivity in perspective: biological consequences. Chem. Biol. Interact. 145, 117-137.
175. Boelsterli, U. A. (2003) Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity. Toxicol. Appl. Pharmacol. 192, 307-322.
176. Walker,G. S., Atherton, J., Bauman, J.,Kohl, C., Lam,W., Reily,M., Lou, Z., and Mutlib, A. (2007) Determination of degradation pathways and kinetics of acyl glucuronides by NMR spectroscopy. Chem. Res. Toxicol. 20, 876-886.
177. Chen, G., Yin, S., Maiti, S., and Shao, X. (2002) 4-Hydroxytamoxifen sulfation metabolism. J. Biochem. Mol. Toxicol. 16, 279-285.
178. Plant, N. (2007) The human cytochrome P450 subfamily: transcriptional regulation, inter-individual variation and interaction networks. Biochim. Biophys. Acta 1770 (3), 478-488.
179. Dickins, M. (2004) Induction of cytochromes P450. Curr. Top. Med. Chem. 4 (16), 1745-1766.
180. Smith, D. A., Dickins, M., Fahmi, O. A., Iwasaki, K., Lee, C., Obach, R. S., Padbury, G., De Morais, S. M., Ripp, S. L., Stevens, J., et al. (2007) The time to move cytochrome P450 induction into mainstream pharmacology is long overdue. Drug Metab. Dispos. 35 (4), 697-698.
181. Hewitt, N. J., Lechon, M. J. G., Houston, J. B., Hallifax, D., Brown, H. S., Maurel, P., Kenna, J. G., Gustavsson, L., Lohmann, C., Skonberg, C., et al. (2007) Primary hepatocytes: current understanding of the regulation ofmetabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab. Rev. 39 (1), 159-234.
182. Mills, J. B., Rose, K. A., Sadagopan, N., Sahi, J., and De Morais, S. M. (2004) Induction of drug metabolism enzymes and MDR1 using a novel human hepatocyte cell line. J. Pharmacol. Exp. Ther. 309, 303-309.
183. Youdim, K. A., Tyman, C. A., Jones, B. C., and Hyland, R. (2007) Induction of cytochrome P450: assessment in an immortalized human hepatocyte cell line (Fa2N4) using a novel higher throughput cocktail assay. Drug Metab. Dispos. 35, 275-282.
184. Mahgoub, A., Idle, J. R.,Dring, L. G., Lancaster, R., and Smith, R. L. (2077) Polymorphic hydroxylation of debrisoquine in man. Lancet 2 (8038), 584-586.
185. Tucker, G. T., Silas, J. H., Iyun, A. O., Lennard, M. S., and Smith, A. J. (2077) Polymorphic hydroxylation of debrisoquine. Lancet 2 (8040), 718.
186. Evans, D. A., Mahgoub, A., Sloan, T. P., Idle, J. R., and Smith, R. L. (2080) A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J. Med. Genet. 17 (2), 102-105.
187. Eichelbaum, M. (2084) Polymorphic drug oxidation in humans. Fed. Proc. 43 (8), 2298-2302.
188. Gut, J., Gasser, R., Dayer, P., Kronbach, T., Catin, T., and Meyer, U. A. (2084) Debrisoquine-type polymorphism of drug oxidation: purification from human liver of a cytochrome P450 isozyme with high activity for bufuralol hydroxylation. FEBS Lett. 173 (2), 287-290.
189. Inaba, T., Nakano, M., Otton, S. V., Mahon, W. A., and Kalow, W. (2084) A human cytochrome P-450 characterized by inhibition studies as the sparteine-debrisoquine monooxygenase. Can. J. Physiol. Pharmacol. 62 (7), 860-862.
190. Hulot, J.-S., Bura, A., Villard, E., Azizi, M., Remones, V., Goyenvalle, C., Aiach, M., Lechat, P., and Gaussem, P. (2006) Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108 (7), 2244-2247.
191. Zandvliet, A. S., Huitema, A. D. R., Copalu, W., Yamada, Y., Tamura, T., Beijnen, J. H., and Schellens, J. H. M. (2007) CYP2C9 and CYP2C19 polymorphic forms are related to increased indisulam exposure and higher risk of severe hematologic toxicity. Clin. Cancer Res. 13 (10), 2970-2976.
192. Westlind-Johnsson, A., Hermann, R., Huennemeye, A., Hauns, B., Lahu, G., Nassr, N., Zech, K., Ingelman-Sundberg, M., and von Richter, O. (2008) Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity. Clin. Pharmacol. Ther. 79 (4), 339-349.
193. Thervet, E., Anglicheau, D., King, B., Schlageter, M.-H., Cassinat, B., Beaune, P., Legendre, C., and Daly, A. K. (2003) Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 76 (8), 1233-1235.
194. MacPhee, I. A. M., Fredericks, S., and Holt, D. W. (2005) Does pharmacogenetics have the potential to allow the individualization of immunosuppressive drug dosing in organ transplantation? Expert Opin. Pharmacother. 6 (15), 2593-2605.
195. Rela,M., Muiesan, P.,Vilca-Melendez, H.,Dhawan, A., Baker,A., Mieli-Vergani, G., and Heaton, N. D. (2099) Auxiliary partial orthotopic liver transplantation for Crigler-Najjar syndrome type I. Ann. Surg. 229 (4), 565-569.
196. Nguyen, T. H., Birraux, J., Wildhaber, B., Myara, A., Trivin, F., Le Coultre, C., Trono, D., and Chardot, C. (2006) Ex vivo lentivirus transduction and immediate transplantation of uncultured hepatocytes for treating hyperbilirubinemic Gunn rat. Transplantation 82 (6), 794-803.
197. Li, Q., Murphree, S. S., Willer, S. S., Bolli, R., and French, B. A. (2098) Gene therapy with bilirubin-UDP-glucuronosyltransferase in the Gunn rat model of Crigler-Najjar syndrome type 1. Hum. Gene Ther. 9 (4), 497-505.
198. Hirschfield, G. M. and Alexander, G. J. (2006) Gilbert's syndrome: an overview for clinical biochemists. Ann. Clin. Biochem. 43 (5), 340-343.
199. Nowell, S. and Falany, C. N. (2006) Pharmacogenetics of human cytosolic sulfotransferases. Oncogene 25 (11), 1673-1678.
200. Hisamuddin, I. M. and Yang, V. W. (2007) Genetic polymorphisms of human flavincontaining monooxygenase 3: implications for drugmetabolism and clinical perspectives. Pharmacogenomics 8 (6), 635-643.
201. Ichida, K., Amaya, Y., Kamatani, N., Nishino, T., Hosoya, T., and Sakai, O. (2097) Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria. J. Clin. Invest. 99 (10), 2391-2397.
202. Yamamoto, T.,Moriwaki, Y., Shibutani, Y., Matsui, K., Ueo, T., Takahashi, S., Tsutsumi, Z., and Hada, T. (2001) Human xanthine dehydrogenase cDNA sequence and protein in an atypical case of type I xanthinuria in comparison with normal subjects. Clin. Chim. Acta 304 (1-2), 153-158.
203. Yamamoto, T., Moriwaki, Y., Takahashi, S., Tsutsumi, Z., Tuneyoshi, K., Matsui, K., Cheng, J., and Hada, T. (2003) Identification of a new point mutation in the human molybdenum cofactor sulfurase gene that is responsible for xanthinuria type II. Metab. Clin. Exp. 52 (11), 1501-1504.
204. Peretz, H., Naamati, M. S., Levartovsky, D., Lagziel, A., Shani, E., Horn, I., Shalev, H., and Landau, D. (2007) Identification and characterization of the first mutation (Arg776Cys) in the C-terminal domain of the human molybdenum cofactor sulfurase (HMCS) associated with type II classical xanthinuria. Mol. Genet. Metab. 91 (1), 23-29.
205. Itoh, K., Masubuchi, A., Sasaki, T., Adachi, M.,Watanabe, N., Nagata, K., Yamazoe, Y., Hiratsuka, M., Mizugaki, M., and Tanaka, Y. (2007) Genetic polymorphism of aldehyde oxidase in donryu rats. Drug Metab. Dispos. 35 (5), 734-739.
206. Brockton, N., Little, J., Sharp, L., and Cotton, S. C. (2000) N-acetyltransferase polymorphisms and colorectal cancer: a HuGE review. Am. J. Epidemiol. 151 (9), 846-861.
207. Benedetti, M. S., Whomsley, R., Espie, P., and Baltes, E. (2004) The role of the efflux transporter P-glycoprotein (P-gp) on the disposition of antiepileptic drugs: implications for drug interactions. In: Focus on Epilepsy Research, Benjamin Shawn, M., (ed.), Nova Science, New York, pp. 199-220.
208. Robey, R. W., Polgar, O., Deeken, J., To, K. W., and Bates, S. E. (2007) ABCG2: determining its relevance in clinical drug resistance. Cancer Metastasis Rev. 26 (1), 39-57.
209. Geier, A., Wagner, M., Dietrich, C. G., and Trauner, M. (2007) Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Biochim. Biophys. Acta Mol. Cell Res. 1773 (3), 283-308.
210. Sakurai, A., Kurata, A., Onishi, Y., Hirano, H., and Ishikawa, T. (2007) Prediction of drug-induced intrahepatic cholestasis: in vitro screening and QSAR analysis of drugs inhibiting the human bile salt export pump. Expert Opin. Drug Saf. 6 (1), 71-86.
211. Mahadevan, D. and Shirahatti, N. (2005) Strategies for targeting the multidrug resistance-1 (MDR1)/P-gp transporter in human malignancies. Curr. Cancer Drug Targets 5 (6), 445-455.
212. Jansen, P. L.M. and Muller, M. (2001) Genetic transport defects as causes of cholestasis. Falk Symposium. (Hepatology) Vol. 117, pp. 27-33.
213. Leschziner, G. D., Andrew, T., Pirmohamed, M., and Johnson, M. R. (2007) ABCB1 genotype and P-gp expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenomics J. 7 (3), 154-179.