High-Throughput Screening for Stability and Inhibitory Activity of Compounds toward Cytochrome P450-Mediated Metabolism

Journal of Pharmaceutical Sciences

Volumn 93, Issue 2, 2004, Pages 239-255

  Ansede, John H ^a   Thakker, Dhiren R ^a  

^a UNIVERSITY OF NORTH CAROLINA   (United States)

Author keywords

CYP; CYP inhibition; Cytochrome P450; High throughput screening; LC MS; Metabolism

Indexed keywords

CYTOCHROME P450;

AEROBIC METABOLISM; COMBINATORIAL CHEMISTRY; DRUG ABSORPTION; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG EXCRETION; DRUG METABOLISM; DRUG SCREENING; DRUG STABILITY; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING; IN VITRO STUDY; SHORT SURVEY; SYNTHESIS;

EID: 0842332512     PISSN: 00223549     EISSN: None     Source Type: Journal    
DOI: 10.1002/jps.10545     Document Type: Short Survey

References (111)

1. Burkhard P, Hommel U, Sanner M, Walkinshaw MD. 1999. The discovery of steroids and other novel FKBP inhibitors using a molecular docking program. J Mol Biol 287:853-858.
2. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW. 1996. Discovering high-affinity ligands for proteins: SAR by NMR. Science 274:1531-1534.
3. Kiyama R, Tamura Y, Watanabe F, Tsuzuki H, Ohtani M, Yodo M. 1999. Homology modeling of gelatinase catalytic domains and docking simulations of novel sulfonamide inhibitors. J Med Chem 42:1723-1738.
4. Broach JR, Thorner J. 1996. High-throughput screening for drug discovery. Nature 384:14-16.
5. Fernandes PB. 1998. Technological advances in high-throughput screening. Curr Opin Chem Biol 2:597-603.
6. Silverman L, Campbell R, Broach JR. 1998. New assay technologies for high-throughput screening. Curr Opin Chem Biol 2:397-403.
7. Gordon EM, Barrett RW, Dower WJ, Fodor SP, Gallop MA. 1994. Applications of combinatorial technologies to drug discovery. 2. Combinatorial organic synthesis, library screening strategies, and future directions. J Med Chem 37:1385-1401.
8. Gallop MA, Barrett RW, Dower WJ, Fodor SP, Gordon EM. 1994. Applications of combinatorial technologies to drug discovery. 1. Background and peptide combinatorial libraries. J Med Chem 37:1233-1251.
9. Fecik RA, Frank KE, Gentry EJ, Menon SR, Mitscher LA, Telikepalli H. 1998. The search for orally active medications through combinatorial chemistry. Med Res Rev 18:149-185.
10. Persidis A. 1998. High-throughput screening. Advances in robotics and miniturization continue to accelerate drug lead identification. Nat Biotechnol 16:488-489.
11. Houston JG. 1997. The impact of automation on high-throughput screening. Methods Find Exp Clin Pharmacol 19:43-45.
12. Houston JG, Banks M. 1997. The chemical-biological interface: Developments in automated and miniaturised screening technology. Curr Opin Biotechnol 8:734-740.
13. Venter JC, Adams MD, Myers EW, et al. 2001. The sequence of the human genome. Science 291:1304-1351.
14. Lander ES, Linton LM, Birren B, et al. 2001. Initial sequencing and analysis of the human genome. Nature 409:860-921.
15. Drews J. 2000. Drug discovery: a historical perspective. Science 287:1960-1964.
16. DiMasi JA, Hansen RW, Grabowski HG. 2003. The price of innovation: New estimates of drug development costs. J Health Econ 22:151-185.
17. Brennan MB. 2000. Drug discovery. Filtering out failures early in the pipeline. Chem Eng News 5:63-73.
18. Prentis RA, Lis Y, Walker SR. 1988. Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964-1985). Br J Clin Pharmacol 25:387-396.
19. Cunningham MJ. 2000. Genomics and proteomics: The new millennium of drug discovery and development. J Pharmacol Toxicol Methods 44:291-300.
20. White RE. 2000. High-throughput screening in drug metabolism and pharmacokinetic support of drug discovery. Annu Rev Pharmacol Toxicol 40:133-157.
21. Bertrand M, Jackson P, Walther B. 2000. Rapid assessment of drug metabolism in the drug discovery process. Eur J Pharm Sci 11(Suppl 2): S61-S72.
22. Roberts SA. 2001. High-throughput screening approaches for investigating drug metabolism and pharmacokinetics. Xenobiotica 31:557-589.
23. Masimirembwa CM, Thompson R, Andersson TB. 2001. In vitro high throughput screening of compounds for favorable metabolic properties in drug discovery. Comb Chem High Throughput Screen 4:245-263.
24. Guengerich FP. 2001. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 14:611-650.
25. Porter TD, Coon MJ. 1991. Cytochrome P-450. Multiplicity of isoforms, substrates, and catalytic and regulatory mechanisms. J Biol Chem 266:13469-13472.
26. White RE, Coon MJ. 1980. Oxygen activation by cytochrome P-450. Annu Rev Biochem 49:315-356.
27. Anzenbacher P, Anzenbacherova E. 2001. Cytochromes P450 and metabolism of xenobiotics. Cell Mol Life Sci 58:737-747.
28. Thummel KE, Wilkinson GR. 1998. In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 38:389-430.
29. Rendic S, Di Carlo FJ. 1997. Human cytochrome P450 enzymes: A status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 29:413-580.
30. Guengerich FP. 1992. Characterization of human cytochrome P450 enzymes. FASEB J 6:745-748.
31. Guengerich FP. 1992. Cytochrome P450: Advances and prospects. FASEB J 6:667-668.
32. Guengerich FP. 1996. In vitro techniques for studying drug metabolism. J Pharmacokinet Biopharm 24:521-533.
33. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. 1994. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: Studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414-423.
34. Green T. 1990. Species differences in carcinogenicity: The role of metabolism in human risk evaluation. Teratog Carcinog Mutagen 10:103-113.
35. Jenden DJ. 1991. Difficulties in using animal data to predict pharmacological response in man. Neurosci Biobehav Rev 15:105-107.
36. Lin JH. 1995. Species similarities and differences in pharmacokinetics. Drug Metab Dispos 23:1008-1021.
37. Ruelius HW. 1987. Extrapolation from animals to man: Predictions, pitfalls and perspectives. Xenobiotica 17:255-265.
38. Guengerich FP. 1997. Comparisons of catalytic selectivity of cytochrome P450 subfamily enzymes from different species. Chem Biol Interact 106:161-182.
39. Lewis DF, Ioannides C, Parke DV. 1998. Cytochromes P450 and species differences in xenobiotic metabolism and activation of carcinogen. Environ Health Perspect 106:633-641.
40. Wrighton SA, VandenBranden M, Ring BJ. 1996. The human drug metabolizing cytochromes P450. J Pharmacokinet Biopharm 24:461-473.
41. Obach RS, Baxter JG, Liston TE, Silber BM, Jones BC, MacIntyre F, Rance DJ, Wastall P. 1997. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther 283:46-58.
42. Ito K, Iwatsubo T, Kanamitsu S, Nakajima Y, Sugiyama Y. 1998. Quantitative prediction of in vivo drug clearance and drug interactions from in vitro data on metabolism, together with binding and transport. Annu Rev Pharmacol Toxicol 38:461-499.
43. Houston JB, Carlile DJ. 1997. Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices. Drug Metab Rev 29:891-922.
44. Obach RS. 1999. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos 27:1350-1359.
45. Korfmacher WA, Palmer CA, Nardo C, Dunn-Meynell K, Grotz D, Cox K, Lin CC, Elicone C, Liu C, Duchoslav E. 1999. Development of an automated mass spectrometry system for the quantitative analysis of liver microsomal incubation samples: A tool for rapid screening of new compounds for metabolic stability. Rapid Commun Mass Spectrom 13:901-907.
46. Lim HK, Stellingweif S, Sisenwine S, Chan KW. 1999. Rapid drug metabolite profiling using fast liquid chromatography, automated multiple-stage mass spectrometry and receptor-binding. J Chromatogr A 831:227-241.
47. van Breemen RB, Nikolic D, Bolton JL. 1998. Metabolic screening using on-line ultrafiltration mass spectrometry. Drug Metab Dispos 26:85-90.
48. Fernandez-Metzler CL, Owens KG, Baillie TA, King RC. 1999. Rapid liquid chromatography with tandem mass spectrometry-based screening procedures for studies on the biotransformation of drug candidates. Drug Metab Dispos 27:32-40.
49. Wring SA, Silver IS, Serabjit-Singh CJ. 2002. Automated quantitative and qualitative analysis of metabolic stability: A process for compound selection during drug discovery. Methods Enzymol 357:285-295.
50. Bu HZ, Poglod M, Micetich RG, Khan JK. 1999. Structure elucidation of three isomeric metabolites of SYN-2836, a novel antifungal agent, in dogs via liquid chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry methodologies. J Mass Spectrom 34:1185-1194.
51. Zhang N, Fountain ST, Bi H, Rossi DT. 2000. Quantification and rapid metabolite identification in drug discovery using API time-of-flight LC/MS. Anal Chem 72:800-806.
52. Eddershaw PJ, Dickins M. 1999. Advances in in vitro drug metabolism screening. PSTT 2:13-19.
53. Janiszewski JS, Rogers KJ, Whalen KM, Cole MJ, Liston TE, Duchoslav E, Fouda HG. 2001. A high-capacity LC/MS system for the bioanalysis of samples generated from plate-based metabolic screening. Anal Chem 73:1495-1501.
54. Gorsky LD, Koop DR, Coon MJ. 1984. On the stoichiometry of the oxidase and monooxygenase reactions catalyzed by liver microsomal cytochrome P-450. Products of oxygen reduction. J Biol Chem 259:6812-6817.
55. Kuthan H, Ullrich V. 1982. Oxidase and oxygenase function of the microsomal cytochrome P450 monooxygenase system. Eur J Biochem 126:583-588.
56. Nordblom GD, Coon MJ. 1977. Hydrogen peroxide formation and stoichiometry of hydroxylation reactions catalyzed by highly purified liver microsomal cytochrome P-450. Arch Biochem Biophys 180:343-347.
57. Kuthan H, Tsuji H, Graf H, Ullrich V. 1978. Generation of superoxide anion as a source of hydrogen peroxide in a reconstituted monooxygenase system. FEBS Lett 91:343-345.
58. Staudt H, Lichtenberger F, Ullrich V. 1974. The role of NADH in uncoupled microsomal monoxygenations. Eur J Biochem 46:99-106.
59. Rashba-Step J, Cederbaum AI. 1994. Generation of reactive oxygen intermediates by human liver microsomes in the presence of NADPH or NADH. Mol Pharmacol 45:150-157.
60. Dike LE, Guarino R, Timmins M. 2000. Development of a high throughput, fluorescent assay system to determine relative rates of metabolism. Drug Metab Rev 32:183.
61. Estabrook RW, Kawano S, Werringloer J, Kuthan H, Tsuji H, Graf H, Ullrich V. 1979. Oxycytochrome P-450: Its breakdown to superoxide for the formation of hydrogen peroxide. Acta Biol Med Ger 38:423-434.
62. Ingelman-Sundberg M, Johansson I. 1984. Mechanisms of hydroxyl radical formation and ethanol oxidation by ethanol-inducible and other forms of rabbit liver microsomal cytochromes P-450. J Biol Chem 259:6447-6458.
63. Thakker DR, Chen C. 2001. Method of screening candidate compounds for susceptibility to oxidative metabolism. U.S. Patent 6,312,917.
64. Kadlubar FF, Morton KC, Ziegler DM. 1973. Microsomal-catalyzed hydroperoxide-dependent C-oxidation of amines. Biochem Biophys Res Commun 54:1255-1261.
65. Rahimtula AD, O'Brien PJ. 1974. Hydroperoxide catalyzed liver microsomal aromatic hydroxylation reactions involving cytochrome P-450. Biochem Biophys Res Commun 60:440-447.
66. Ellin A, Orrenius S. 1975. Hydroperoxide-supported cytochrome P-450-linked fatty acid hydroxylation in liver microsomes. FEBS Lett 50:378-381.
67. Rahimtula AD, O'Brien PJ. 1975. Hydroperoxide dependent O-dealkylation reactions catalyzed by liver microsomal cytochrome P450. Biochem Biophys Res Commun 62:268-275.
68. Hrycay EG, Gustafsson JA, Ingelman-Sundberg M, Ernster L. 1975. Sodium periodate, sodium chlorite, and organic hydroperoxides as hydroxylating agents in hepatic microsomal steroid hydroxylation reactions catalyzed by cytochrome P-450. FEBS Lett 56:161-165.
69. 2 as hydroxylating agents in steroid hydroxylation reactions catalyzed by partially purified cytochrome P-450. Biochem Biophys Res Commun 66:209-216.
70. Trubetskoy DV, Thompson DV, Lowery RG. 2000. Novel in vitro screen for CYP 2D6. Drug Metab Rev 32:209.
71. Lindon JC, Nicholson JK, Wilson ID. 1996. The development and application of coupled HPLC-NMR spectroscopy. Adv Chromatogr 36:315-382.
72. Sidelmann UG, Lenz EM, Spraul M, Hofmann M, Troke J, Sanderson PN, Lindon JC, Wilson ID, Nicholson JK. 1996. 750 MHz HPLC-NMR spectroscopic studies on the separation and characterization of the positional isomers of the glucuronides of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid. Anal Chem 68:106-110.
73. Lindon JC, Nicholson JK, Sidelmann UG, Wilson ID. 1997. Directly coupled HPLC-NMR and its application to drug metabolism. Drug Metab Rev 29:705-746.
74. Shockcor JP, Wurm RM, Frick LW, Sanderson PN, Farrant RD, Sweatman BC, Lindon JC. 1996. HPLC-NMR identification of the human urinary metabolites of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, a nucleoside analogue active against human immunodeficiency virus (HIV). Xenobiotica 26:189-199.
75. Shockcor JP, Silver IS, Wurm RM, Sanderson PN, Farrant RD, Sweatman BC, Lindon JC. 1996. Characterization of in vitro metabolites from human liver microsomes using directly coupled HPLC-NMR: Application to a phenoxathiin monoamine oxidase-A inhibitor. Xenobiotica 26:41-48.
76. Spraul M, Hofmann M, Wilson ID, Lenz E, Nicholson JK, Lindon JC. 1993. Coupling of HPLC with 19F- and 1H-NMR spectroscopy to investigate the human urinary excretion of flurbiprofen metabolites. J Pharm Biomed Anal 11:1009-1015.
77. Nicholls AW, Lindon JC, Farrant RD, Shockcor JP, Wilson ID, Nicholson JK. 1999. Directly-coupled HPLC-NMR spectroscopic studies of metabolism and futile deacetylation of phenacetin in the rat. J Pharm Biomed Anal 20:865-873.
78. Shockcor JP, Unger SE, Wilson ID, Foxall PJ, Nicholson JK, Lindon JC. 1996. Combined HPLC, NMR spectroscopy, and ion-trap mass spectrometry with application to the detection and characterization of xenobiotic and endogenous metabolites in human urine. Anal Chem 68:4431-4435.
79. Burton KI, Everett JR, Newman MJ, Pullen FS, Richards DS, Swanson AG. 1997. On-line liquid chromatography coupled with high field NMR and mass spectrometry (LC-NMR-MS): A new technique for drug metabolite structure elucidation. J Pharm Biomed Anal 15:1903-1912.
80. Shockcor JP, Unger SE, Savina P, Nicholson JK, Lindon JC. 2000. Application of directly coupled LC-NMR-MS to the structural elucidation of metabolites of the HIV-1 reverse-transcriptase inhibitor BW935U83. J Chromatogr B Biomed Sci Appl 748:269-279.
81. Sidelmann UG, Bjornsdottir I, Shockcor JP, Hansen SH, Lindon JC, Nicholson JK. 2001. Directly coupled HPLC-NMR and HPLC-MS approaches for the rapid characterisation of drug metabolites in urine: Application to the human metabolism of naproxen. J Pharm Biomed Anal 24:569-579.
82. Holt RM, Newman MJ, Pullen FS, Richards DS, Swanson AG. 1997. High-performance liquid chromatography/NMR spectrometry/mass spectrometry: Further advances in hyphenated technology. J Mass Spectrom 32:64-70.
83. Zhang KE, Hee B, Lee CA, Liang B, Potts BC. 2001. Liquid chromatography-mass spectrometry and liquid chromatography-NMR characterization of in vitro metabolites of a potent and irreversible peptidomimetic inhibitor of rhinovirus 3C protease. Drug Metab Dispos 29:729-734.
84. Fisher MB, Jackson D, Kaerner A, Wrighton SA, Borel AG. 2002. Characterization by liquid chromatography-nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry of two coupled oxidative-conjugative metabolic pathways for 7-ethoxycoumarin in human liver microsomes treated with alamethicin. Drug Metab Dispos 30:270-275.
85. Lopez LL, Yu X, Cui D, Davis MR. 1998. Identification of drug metabolites in biological matrices by intelligent automated liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 12:1756-1760.
86. Chen H, Shockcor J, Chen W, Espina R, Gan LS, Mutlib AE. 2002. Delineating novel metabolic pathways of DPC 963, a non-nucleoside reverse transcriptase inhibitor, in rats. Characterization of glutathione conjugates of postulated oxirene and benzoquinone imine intermediates by LC/MS and LC/NMR. Chem Res Toxicol 15:388-399.
87. Mutlib AE, Shockcor J, Chen SY, Espina RJ, Pinto DJ, Orwat MJ, Prakash SR, Gan LS. 2002. Disposition of 1-[3-(aminomethyl)phenyl]-N[3-fluoro-2′ -(methylsulfonyl)-[1,1′-biphenyl]-4-yl]-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (DPC 423) by novel metabolic pathways. Characterization of unusual metabolites by liquid chromatography/mass spectrometry and NMR. Chem Res Toxicol 15:48-62.
88. Guengerich FP. 1997. Role of cytochrome P450 enzymes in drug-drug interactions. Adv Pharmacol 43:7-35.
89. Murray M. 1992. P450 enzymes. Inhibition mechanisms, genetic regulation and effects of liver disease. Clin Pharmacokinet 23:132-146.
90. Mullins ME, Horowitz BZ, Linden DH, Smith GW, Norton RL, Stump J. 1998. Life-threatening interaction of mibefradil and beta-blockers with dihydropyridine calcium channel blockers. JAMA 280:157-158.
91. Ayrton J, Plumb R, Leavens WJ, Mallett D, Dickins M, Dear GJ. 1998. Application of a generic fast gradient liquid chromatography tandem mass spectrometry method for the analysis of cytochrome P450 probe substrates. Rapid Commun Mass Spectrom 12:217-224.
92. Dierks EA, Stams KR, Lim HK, Cornelius G, Zhang H, Ball SE. 2001. 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.
93. Miller VP, Stresser DM, Blanchard AP, Turner S, Crespi CL. 2000. Fluorometric high-throughput screening for inhibitors of cytochrome P450. Ann NY Acad Sci 919:26-32.
94. Crespi CL, Stresser DM. 2000. Fluorometric screening for metabolism-based drug-drug interactions. J Pharmacol Toxicol Methods 44:325-331.
95. Crespi CL, Miller VP, Penman BW. 1997. Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450. Anal Biochem 248:188-190.
96. Moody GC, Griffin SJ, Mather AN, McGinnity DF, Riley RJ. 1999. Fully automated analysis of activities catalysed by the major human liver cytochrome P450 (CYP) enzymes: assessment of human CYP inhibition potential. Xenobiotica 29:53-75.
97. Rodrigues AD, Surber BW, Yao Y, Wong SL, Roberts EM. 1997. [O-ethyl 14C]phenacetin O-deethylase activity in human liver microsomes. Drug Metab Dispos 25:1097-1100.
98. Delaporte E, Slaughter DE, Egan MA, Gatto GJ, Santos A, Shelley J, Price E, Howells L, Dean DC, Rodrigues AD. 2001. The potential for CYP2D6 inhibition screening using a novel scintillation proximity assay-based approach. J Biomol Screen 6:225-231.
99. Wang RW, Newton DJ, Liu N, Atkins WM, Lu AY. 2000. Human cytochrome P-450 3A4: In vitro drug-drug interaction patterns are substrate-dependent. Drug Metab Dispos 28:360-366.
100. Kenworthy KE, Bloomer JC, Clarke SE, Houston JB. 1999. CYP3A4 drug interactions: Correlation of 10 in vitro probe substrates. Br J Clin Pharmacol 48:716-727.
101. Korzekwa KR, Krishnamachary N, Shou M, Ogai A, Parise RA, Rettie AE, Gonzalez FJ, Tracy TS. 1998. Evaluation of atypical cytochrome P450 kinetics with two-substrate models: Evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites. Biochemistry 37:4137-4147.
102. Venhorst J, Onderwater RC, Meerman JH, Vermeulen NP, Commandeur JN. 2000. Evaluation of a novel high-throughput assay for cytochrome P450 2D6 using 7-methoxy-4-(aminomethyl)-coumarin. Eur J Pharm Sci 12:151-158.
103. Nomeir AA, Ruegg C, Shoemaker M, Favreau LV, Palamanda JR, Silber P, Lin CC. 2001. Inhibition of CYP3A4 in a rapid microtiter plate assay using recombinant enzyme and in human liver microsomes using conventional substrates. Drug Metab Dispos 29:748-753.
104. Chauret N, Tremblay N, Lackman RL, Gauthier JY, Silva JM, Marois J, Yergey JA, Nicoll-Griffith DA. 1999. Description of a 96-well plate assay to measure cytochrome P4503A inhibition in human liver microsomes using a selective fluorescent probe. Anal Biochem 276:215-226.
105. Chu I, Favreau L, Soares T, Lin C, Nomeir AA. 2000. Validation of higher-throughput high-performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry assays to conduct cytochrome P450s CYP2D6 and CYP3A4 enzyme inhibition studies in human liver microsomes. Rapid Commun Mass Spectrom 14:207-214.
106. Rodrigues AD, Kukulka MJ, Surber BW, Thomas SB, Uchic JT, Rotert GA, Michel G, Thome-Kromer B, Machinist JM. 1994. Measurement of liver microsomal cytochrome p450 (CYP2D6) activity using [O-methyl-14C]dextromethorphan. Anal Biochem 219:309-320.
107. Rodrigues AD, Kukulka MJ, Roberts EM, Ouellet D, Rodgers TR. 1996. [O-methyl 14C]naproxen O-demethylase activity in human liver microsomes: Evidence for the involvement of cytochrome P4501A2 and P4502C9/10. Drug Metab Dispos 24:126-136.
108. Yasumori T, Nagata K, Yang SK, Chen LS, Murayama N, Yamazoe Y, Kato R. 1993. Cytochrome P450 mediated metabolism of diazepam in human and rat: Involvement of human CYP2C in N-demethylation in the substrate concentration-dependent manner. Pharmacogenetics 3:291-301.
109. Riley RJ, Howbrook D. 1997. In vitro analysis of the activity of the major human hepatic CYP enzyme (CYP3A4) using [N-methyl-14C]-erythromycin. J Pharmacol Toxicol Methods 38:189-193.
110. Guengerich FP. 2001. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 14:611-650.
111. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. 1994. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: Studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414-423.