Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the "cocktail" approach

Clinical Pharmacology and Therapeutics

Volumn 81, Issue 2, 2007, Pages 270-283

  Fuhr, U ^a,b   Jetter, A ^a   Kirchheiner, J ^c  

^a UNIVERSITY OF COLOGNE   (Germany)

^b Phynix GmbH and Co KG   (Germany)

^c UNIVERSITY OF ULM   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CAFFEINE; CHLORZOXAZONE; CYTOCHROME P450 1A2; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 2E1; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; DEBRISOQUINE; DEXTROMETHORPHAN; DICLOFENAC; DIGOXIN; DRUG METABOLIZING ENZYME; ERYTHROMYCIN; FLUCONAZOLE; FLURBIPROFEN; GLYCOPROTEIN P; LOSARTAN; MEPHENYTOIN; METOPROLOL; MIDAZOLAM; OMEPRAZOLE; PARAXANTHINE; TOLBUTAMIDE; UNINDEXED DRUG; VITAMIN K GROUP; WARFARIN;

AREA UNDER THE CURVE; DRUG ACTIVITY; DRUG CLEARANCE; DRUG DISPOSITION; DRUG DOSE REDUCTION; DRUG ELIMINATION; DRUG HYDROXYLATION; DRUG INFORMATION; DRUG METABOLISM; DRUG SCREENING; DRUG SELF ADMINISTRATION; DRUG TRANSPORT; ELECTROCARDIOGRAM; ENZYME ACTIVITY; ENZYME SUBSTRATE; HUMAN; HYPOGLYCEMIA; INTERNATIONAL NORMALIZED RATIO; LABORATORY TEST; PHENOTYPE; PHYSICAL EXAMINATION; PRIORITY JOURNAL; PULSE OXIMETRY; REVIEW; SEDATION; SIDE EFFECT; VALIDATION STUDY; VITAL SIGN;

ADMINISTRATION, ORAL; ATP-BINDING CASSETTE TRANSPORTERS; CAFFEINE; CYTOCHROME P-450 ENZYME SYSTEM; DEBRISOQUIN; HUMANS; PHARMACEUTICAL PREPARATIONS; PHENOTYPE; THEOPHYLLINE; TOLBUTAMIDE;

EID: 33846607427     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1038/sj.clpt.6100050     Document Type: Review

References (114)

1. Streetman, D.S., Bertino, J.S. Jr & Nafziger, A.N. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 10, 187-216 (2000).
2. Tucker, G.T., Houston, J.B. & Huang, S.M. Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential-toward a consensus. Clin. Pharmacol. Ther. 70, 103-114 (2001).
3. Wilkinson, G.R. In Vivo Probes for Studying Induction and Inhibition of Cytochrome P450 Enzymes in Humans, (Marcel Dekker, Inc., New York, (2001).
4. Özdemir, V., Kalow, W., Tang, B.K., Paterson, A.D., Walker, S.E. & Endrenyi, L. et al. Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics 10, 373-388 (2000).
5. Kashuba, A.D., Nafziger, A.N., Kearns, G.L., Leeder, J.S., Shirey, C.S. & Gotschall, R. et al. Quantification of intraindividual variability and the influence of menstrual cycle phase on CYP2D6 activity as measured by dextromethorphan phenotyping. Pharmacogenetics 8, 403-410 (1998).
6. Kashuba, A.D., Bertino, J.S. Jr, Rocci, M.L. Jr, Kulawy, R.W., Beck, D.J. & Nafziger, A.N. Quantification of 3-month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A activity as measured by phenotyping with intravenous midazolam. Clin. Pharmacol. Ther. 64, 269-277 (1998).
7. Kashuba, A.D., Bertino, J.S. Jr, Kearns, G.L., Leeder, J.S., James, A.W. & Gotschall, R. et al. Quantitation of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping. Clin. Pharmacol. Ther. 63, 540-551 (1998).
8. Wang, L. & Weinshilboum, R. Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions. Oncogene 25, 1629-1638 (2006).
9. Fuhr, U., Weiss, M., Kroemer, H.K., Neugebauer, G., Rameis, H. & Weber, W. et al. Systematic screening for pharmacokinetic interactions during drug development. Int. J. Clin. Pharmacol. Ther. 34, 139-151 (1996).
10. Park, G.R. Molecular mechanisms of drug metabolism in the critically ill. Br. J. Anaesth. 77, 49 (1996).
11. Daly, A.K. Pharmacogenetics of the major polymorphic metabolizing enzymes. Fundam. Clin. Pharmacol. 17, 27-41 (2003).
12. Kirchheiner, J., Fuhr, U. & Brockmoller, J. Pharmacogenetics-based therapeutic recommendations - ready for clinical practice? Nat. Rev. Drug. Discov. 4, 639-647 (2005).
13. Tantcheva-Poor, I., Zaigler, M., Rietbrock, S. & Fuhr, U. Estimation of cytochrome P-450 CYP1A2 activity in 863 healthy Caucasians using a saliva-based caffeine test. Pharmacogenetics 9, 131-144 (1999).
14. Faber, M.S. & Fuhr, U. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin. Pharmacol. Ther. 76, 178-184 (2004).
15. Aklillu, E., Herrlin, K., Gustafsson, L.L., Bertilsson, L. & Ingelman-Sundberg, M. Evidence for environmental influence on CYP2D6-catalysed debrisoquine hydroxylation as demonstrated by phenotyping and genotyping of Ethiopians living in Ethiopia or in Sweden. Pharmacogenetics 12, 375-383 (2002).
16. Watkins, P.B. Noninvasive tests of CYP3A enzymes. Pharmacogenetics 4, 171-184 (1994).
17. Zaigler, M., Tantcheva-Poor, I. & Fuhr, U. Problems and perspectives of phenotyping for drug-metabolizing enzymes in man. Int. J. Clin. Pharmacol. Ther. 38, 1-9 (2000).
18. Kirchheiner, J., Bauer, S., Meineke, I., Rohde, W., Prang, V. & Meisel, C. et al. Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers. Pharmacogenetics 12, 101-109 (2002).
19. Jetter, A., Kinzig-Schippers, M., Skott, A., Lazar, A., Tomalik-Scharte, D. & Kirchheiner, J. et al. Cytochrome P450 2C9 phenotyping using low-dose tolbutamide. Eur. J. Clin. Pharmacol. 60, 165-171 (2004).
20. Jetter, A., Kinzig-Schippers, M., Illauer, M., Hermann, R., Erb, K. & Borlak, J. et al. Phenotyping of N-acetyltransferase type 2 by caffeine from uncontrolled dietary exposure. Eur. J. Clin. Pharmacol. 60, 17-21 (2004).
21. Galteau, M.M. & Shamsa, F. Urinary 6beta-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals. Eur. J. Clin. Pharmacol. 59, 713-733 (2003).
22. Bodin, K., Bretillon, L., Aden, Y., Bertilsson, L., Broome, U. & Einarsson, C. et al. Antiepileptic drugs increase plasma levels of 4beta-hydroxy-cholesterol in humans: evidence for involvement of cytochrome p450 3A4. J. Biol. Chem. 276, 38685-38689 (2001).
23. Klaassen, T., Jetter, A., Tomalik-Scharte, D., Kasel, D., Harlfinger, S. & Kirchheiner, J. et al. Urinary metrics to phenotype for CYP2C19 and CYP2B6. Clin. Exp. Pharmacol. Physiol. 31(Suppl): A145 (2004).
24. Laine, K., Tybring, G. & Bertilsson, L. No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects. Clin. Pharmacol. Ther. 68, 151-159 (2000).
25. Tomalik-Scharte, D., Jetter, A., Kinzig-Schippers, M., Skott, A., Sorgel, F. & Klaassen, T. et al. Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers. Drug Metab. Dispos. 33, 1859-1866 (2005).
26. Diletti, E., Hauschke, D. & Steinijans, V.W. Sample size determination for bioequivalence assessment by means of confidence intervals. Int. J. Clin. Pharmacol. Ther. Toxicol. 29, 1-8 (1991).
27. Fuhr, U., Rost, K.L., Engelhardt, R., Sachs, M., Liermann, D. & Belloc, C. et al. Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations. Pharmacogenetics 6, 159-176 (1996).
28. Veronese, M.E., Miners, J.O., Randles, D., Gregov, D. & Birkett, D.J. Validation of the tolbutamide metabolic ratio for population screening with use of sulfaphenazole to produce model phenotypic poor metabolizers. Clin. Pharmacol. Ther. 47, 403-411 (1990).
29. Jabrane, W., Malchau, G., Kinzig-Schippers, M., Tönnes, E., Jetter, A. & Lück, H. et al. A pilot study to address the role of renal function in phenotyping for intestinal transporter activity using oral marker substrates Proc. of the 6th Congress of the European Association for Clinical Pharmacology and Therapeutics (EACPT), Istanbul. 2003.
30. Özdemir, M., Crewe, K.H., Tucker, G.T. & Rostami-Hodjegan, A. Assessment of in vivo CYP2D6 activity: differential sensitivity of commonly used probes to urine pH. J. Clin. Pharmacol. 44, 1398-1404 (2004).
31. Kirchheiner, J., Klein, C., Meineke, I., Sasse, J., Zanger, U.M. & Murdter, T.E. et al. Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics 13, 619-626 (2003).
32. Kirchheiner, J., Roots, I., Goldammer, M., Rosenkranz, B. & Brockmoller, J. Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin. Pharmacokinet. 44, 1209-1225 (2005).
33. Dempsey, D., Tutka, P., Jacob, P. III, Allen, F., Schoedel, K. & Tyndale, R.F. et al. Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin. Pharmacol. Ther. 76, 64-72 (2004).
34. Pelkonen, O., Rautio, A., Raunio, H. & Pasanen, M. CYP2A6: a human coumarin 7-hydroxylase. Toxicology 144, 139-147 (2000).
35. Ho, R.H. & Kim, R.B. Transporters and drug therapy: implications for drug disposition and disease. Clin. Pharmacol. Ther. 78, 260-277 (2005).
36. Tanaka, E., Kurata, N. & Yasuhara, H. How useful is the "cocktail approach" for evaluating human hepatic drug metabolizing capacity using cytochrome P450 phenotyping probes in vivo? J. Clin. Pharm Ther. 28, 157-165 (2003).
37. Fuhr, U. & Rost, K.L. Simple and reliable CYP1A2 phenotyping by the paraxanthine/caffeine ratio in plasma and in saliva. Pharmacogenetics 4, 109-116 (1994).
38. Rostami-Hodjegan, A., Nurminen, S., Jackson, P.R. & Tucker, G.T. Caffeine urinary metabolite ratios as markers of enzyme activity: a theoretical assessment. Pharmacogenetics 6, 121-149 (1996).
39. Linder, M.W., Looney, S., Adams, J.E. III, Johnson, N., Antonino-Green, D. & Lacefield, N. et al. Warfarin dose adjustments based on CYP2C9 genetic polymorphisms. J. Thromb. Thrombolysis. 14, 227-232 (2002).
40. Chainuvati, S., Nafziger, A.N., Leeder, J.S., Gaedigk, A., Kearns, G.L. & Sellers, E. et al. Combined phenotypic assessment of cytochrome p450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the "Cooperstown 5+1 cocktail". Clin. Pharmacol. Ther. 74, 437-447 (2003).
41. Bruce, M.A., Hall, S.D., Haehner-Daniels, B.D. & Gorski, J.C. In vivo effect of clarithromycin on multiple cytochrome P450s. Drug Metab. Dispos. 29, 1023-1028 (2001).
42. Yasar, U., Forslund-Bergengren, C., Tybring, G., Dorado, P., Llerena, A. & Sjoqvist, F. et al. Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype. Clin. Pharmacol. Ther. 71, 89-98 (2002).
43. Meadowcroft, A.M., Williamson, K.M., Patterson, J.H., Hinderliter, A.L. & Pieper, J.A. The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers. J. Clin. Pharmacol. 39, 418-424 (1999).
44. Greenblatt, D.J., von Moltke, L.L., Perloff, E.S., Luo, Y., Harmatz, J.S. & Zinny, M.A. Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: in vitro and clinical studies. Clin. Pharmacol. Ther. 79, 125-133 (2006).
45. Zgheib, N.K., Frye, R.F., Tracy, T.S., Romkes, M. & Branch, R.A. Validation of incorporating flurbiprofen into the Pittsburgh cocktail. Clin. Pharmacol. Ther. 80, 257-263 (2006).
46. Lee, C.R., Pieper, J.A., Frye, R.F., Hinderliter, A.L., Blaisdell, J.A. & Goldstein, J.A. Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans. J. Clin. Pharmacol. 43, 84-91 (2003).
47. Krösser, S., Neugebauer, R., Dolgos, H., Fluck, M., Rost, K.L. & Kovar, A. Investigation of sarizotan's impact on the pharmacokinetics of probe drugs for major cytochrome P450 isoenzymes: a combined cocktail trial. Eur. J. Clin. Pharmacol. 62, 277-284 (2006).
48. Yasar, U., Eliasson, E., Forslund-Bergengren, C., Tybring, G., Gadd, M. & Sjoqvist, F. et al. The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro. Eur. J. Clin. Pharmacol. 57, 729-735 (2001).
49. Kirchheiner, J., Meineke, I., Steinbach, N., Meisel, C., Roots, I. & Brockmoller, J. Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans. Br. J. Clin. Pharmacol. 55, 51-61 (2003).
50. Rost, K.L., Fuhr, U., Thomsen, T., Zaigler, M., Brockmoller, J. & Bohnemeier, H. et al. Omeprazole weakly inhibits CYP1A2 activity in man. Int. J. Clin. Pharmacol. Ther. 37, 567-574 (1999).
51. Rost, K.L., Brosicke, H., Heinemeyer, G. & Roots, I. Specific and dose-dependent enzyme induction by omeprazole in human beings. Hepatology 20, 1204-1212 (1994).
52. Borges, S., Li, L., Hamman, M.A., Jones, D.R., Hall, S.D. & Gorski, J.C. Dextromethorphan to dextrorphan urinary metabolic ratio does not reflect dextromethorphan oral clearance. Drug Metab. Dispos. 33, 1052-1055 (2005).
53. Zhou, H., Tong, Z. & McLeod, J.F. "Cocktail" approaches and strategies in drug development: valuable tool or flawed science? J. Clin. Pharmacol. 44, 120-134 (2004).
54. McGourty, J.C., Silas, J.H., Lennard, M.S., Tucker, G.T. & Woods, H.F. Metoprolol metabolism and debrisoquine oxidation polymorphism-population and family studies. Br. J. Clin. Pharmacol. 20, 555-566 (1985).
55. Mishin, V.M., Rosman, A.S., Basu, P., Kessova, I., Oneta, C.M. & Lieber, C.S. Chlorzoxazone pharmacokinetics as a marker of hepatic cytochrome P4502E1 in humans. Am. J. Gastroenterol. 93, 2154-2161 (1998).
56. Frye, R.F., Adedoyin, A., Mauro, K., Matzke, G.R. & Branch, R.A. Use of chlorzoxazone as an in vivo probe of cytochrome P450 2E1: choice of dose and phenotypic trait measure. J. Clin. Pharmacol. 38, 82-89 (1998).
57. Palmer, J.L., Scott, R.J., Gibson, A., Dickins, M. & Pleasance, S. An interaction between the cytochrome P450 probe substrates chlorzoxazone (CYP2E1) and midazolam (CYP3A). Br. J. Clin. Pharmacol. 52, 555-561 (2001).
58. Chen, Y.C., Gotzkowsky, S.K., Nafziger, A.N., Kulawy, R.W., Rocci, M.L. Jr & Bertino, J.S. Jr et al. Poor correlation between 6beta-hydroxycortisol: cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity. Br. J. Clin. Pharmacol. 62, 187-195 (2006).
59. Wrighton, S.A., Brian, W.R., Sari, M.A., Iwasaki, M., Guengerich, F.P. & Raucy, J.L. et al. Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Mol. Pharmacol. 38, 207-213 (1990).
60. He, P., Court, M.H., Greenblatt, D.J. & Von Moltke, L.L. Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin. Pharmacol. Ther. 77, 373-387 (2005).
61. Tsunoda, S.M., Velez, R.L., von Moltke, L.L. & Greenblatt, D.J. Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Clin. Pharmacol. Ther. 66, 461-471 (1999).
62. Chaobal, H.N. & Kharasch, E.D. Single-point sampling for assessment of constitutive, induced, and inhibited cytochrome P450 3A activity with alfentanil or midazolam. Clin. Pharmacol. Ther. 78, 529-539 (2005).
63. Gorski, J.C., Jones, D.R., Haehner-Daniels, B.D., Hamman, M.A., O'Mara, E.M. Jr & Hall, S.D. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin. Pharmacol. Ther. 64, 133-143 (1998).
64. Jabrane, W., Fuhr, U., Kinzig-Schippers, M., Jetter, A., Hering, U. & Walchner-Bonjean, M. et al. Sequential i.v. and oral administration of midazolam to estimate hepatic and intestinal CYP3A4 activity. Eur. J. Clin. Pharmacol. 57, A35 (2001).
65. Lee, J.I., Chaves-Gnecco, D., Amico, J.A., Kroboth, P.D., Wilson, J.W. & Frye, R.F. Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping. Clin. Pharmacol. Ther. 72, 718-728 (2002).
66. von Richter, O., Burk, O., Fromm, M.F., Thon, K.P., Eichelbaum, M. & Kivisto, K.T. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin. Pharmacol. Ther. 75, 172-183 (2004).
67. Veronese, M.L., Gillen, L.P., Burke, J.P., Dorval, E.P., Hauck, W.W. & Pequignot, E. et al. Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice. J. Clin. Pharmacol. 43, 831-839 (2003).
68. Wandel, C., Bocker, R.H., Bohrer, H., deVries, J.X., Hofmann, W. & Walter, K et al. Relationship between hepatic cytochrome P450 3A content and activity and the disposition of midazolam administered orally. Drug Metab. Dispos. 26, 110-114 (1998).
69. Rogers, J.F., Nafziger, A.N., Kashuba, A.D., Streetman, D.S., Rocci, M.L. Jr & Choo, E.F. et al. Single plasma concentrations of 10-hydroxymidazolam or the ratio of 1′-hydroxymidazolam:midazolam do not predict midazolam clearance in healthy subjects. J. Clin. Pharmacol. 42, 1079-1082 (2002).
70. Eap, C.B., Buclin, T., Cucchia, G., Zullino, D., Hustert, E. & Bleiber, G. et al. Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity. Eur. J. Clin Pharmacol. 60, 237-246 (2004).
71. Kinirons, M.T., O'Shea, D., Kim, R.B., Groopman, J.D., Thummel, K.E. & Wood, A.J. et al. Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A. Clin. Pharmacol. Ther. 66, 224-231 (1999).
72. Kurnik, D., Wood, A.J. & Wilkinson, G.R. The erythromycin breath test reflects P-glycoprotein function independently of cytochrome P450 3A activity. Clin. Pharmacol. Ther. 80, 228-234 (2006).
73. Frye, R.F., Matzke, G.R., Adedoyin, A., Porter, J.A. & Branch, R.A. Validation of the five-drug "Pittsburgh cocktail" approach for assessment of selective regulation of drug-metabolizing enzymes. Clin. Pharmacol. Ther. 62, 365-376 (1997).
74. Sharma, A., Pilote, S., Belanger, P.M., Arsenault, M. & Hamelin, B.A. A convenient five-drug cocktail for the assessment of major drug metabolizing enzymes: a pilot study. Br. J. Clin. Pharmacol. 58, 288-297 (2004).
75. Gass, R.J., Gal, J., Fogle, P.W., Detmar-Hanna, D. & Gerber, J.G. Neither dapsone hydroxylation nor cortisol 6beta-hydroxylation detects the inhibition of CYP3A4 by HIV-1 protease inhibitors. Eur. J. Clin. Pharmacol. 54, 741-747 (1998).
76. Mirghani, R.A., Ericsson, O., Tybring, G., Gustafsson, L.L. & Bertilsson, L. Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man. Eur. J. Clin. Pharmacol. 59, 23-28 (2003).
77. Christensen, M., Andersson, K., Dalen, P., Mirghani, R.A., Muirhead, G.J. & Nordmark, A. et al. The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin. Pharmacol. Ther. 73, 517-528 (2003).
78. Kalow, W. & Tang, B.K. The use of caffeine for enzyme assays: a critical appraisal. Clin. Pharmacol. Ther. 53, 503-514 (1993).
79. Nyeki, A., Buclin, T., Biollaz, J. & Decosterd, L.A. NAT2 and CYP1A2 phenotyping with caffeine: head-to-head comparison of AFMU vs AAMU in the urine metabolite ratios. Br. J. Clin. Pharmacol. 55, 62-67 (2003).
80. Jetter, A., Kinzig-Schippers, M., Illauer, M., Tomalik-Scharte, D., Sörgel, F. & Fuhr, U. When should urine samples for NAT2 phenotyping with caffeine be collected? Clin. Pharmacol. Ther. 75, 69 (2004).
81. Xie, H.G., Xu, Z.H., Ou-Yang, D.S., Shu, Y., Yang, D.L. & Wang, J.S. et al. Meta-analysis of phenotype and genotype of NAT2 deficiency in Chinese populations. Pharmacogenetics 7, 503-514 (1997).
82. Meisel, P., Arndt, D., Scheuch, E., Klebingat, K.J. & Siegmund, W. Prediction of metabolic activity from genotype: the gene-dose effect of N-acetyltransferase. Ther. Drug Monit. 23, 9-14 (2001).
83. Ieiri, I., Takane, H. & Otsubo, K. The MDR1 (ABCB1) gene polymorphism and its clinical implications. Clin. Pharmacokinet. 43, 553-576 (2004).
84. Taipalensuu, J., Tavelin, S., Lazorova, L., Svensson, A.C. & Artursson, P. Exploring the quantitative relationship between the level of MDR1 transcript, protein and function using digoxin as a marker of MDR1-dependent drug efflux activity. Eur. J. Pharm. Sci. 21, 69-75 (2004).
85. Johne, A., Kopke, K., Gerloff, T., Mai, I., Rietbrock, S. & Meisel, C. et al. Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin. Pharmacol. Ther. 72, 584-594 (2002).
86. Greiner, B., Eichelbaum, M., Fritz, P., Kreichgauer, H.P., von Richter, O. & Zundler, J. et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J. Clin. Invest. 104, 147-153 (1999).
87. Drescher, S., Schaeffeler, E., Hitzl, M., Hofmann, U., Schwab, M. & Brinkmann, U. et al. MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br. J. Clin. Pharmacol. 53, 526-534 (2002).
88. Hamman, M.A., Bruce, M.A., Haehner-Daniels, B.D. & Hall, S.D. The effect of rifampin administration on the disposition of fexofenadine. Clin. Pharmacol. Ther. 69, 114-121 (2001).
89. Zhang, W.X., Chen, G.L., Zhang, W., Tan, Z.R., Liu, J. & Zhou, G. et al. MDR1 genotype do not influence the absorption of a single oral dose of 100 mg talinolol in healthy Chinese males. Clin. Chim. Acta. 359, 46-52 (2005).
90. Granfors, M.T., Backman, J.T., Neuvonen, M., Ahonen, J. & Neuvonen, P.J. Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction. Clin. Pharmacol. Ther. 75, 331-341 (2004).
91. Galetin, A., Ito, K., Hallifax, D. & Houston, J.B. CYP3A4 substrate selection and substitution in the prediction of potential drug-drug interactions. J. Pharmacol. Exp. Ther. 314, 180-190 (2005).
92. Schellens, J.H., van der Wart, J.H., Brugman, M. & Breimer, D.D. Influence of enzyme induction and inhibition on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in humans as assessed by a "cocktail" study design. J. Pharmacol. Exp. Ther. 249, 638-645 (1989).
93. Scott, R.J., Palmer, J., Lewis, I.A. & Pleasance, S. Determination of a 'GW cocktail' of cytochrome P450 probe substrates and their metabolites in plasma and urine using automated solid phase extraction and fast gradient liquid chromatography tandem mass spectrometry. Rapid Commun. Mass Spectrom. 13, 2305-2319 (1999).
94. Yin, O.Q., Lam, S.S., Lo, C.M. & Chow, M.S. Rapid determination of five probe drugs and their metabolites in human plasma and urine by liquid chromatography/tandem mass spectrometry: application to cytochrome P450 phenotyping studies. Rapid Commun. Mass Spectrom. 18, 2921-2933 (2004).
95. Jerdi, M.C., Daali, Y., Oestreicher, M.K., Cherkaoui, S. & Dayer, P. A simplified analytical method for a phenotyping cocktail of major CYP450 biotransformation routes. J. Pharm. Biomed. Anal. 35, 1203-1212 (2004).
96. Steinijans, V.W., Hartmann, M., Huber, R. & Radtke, H.W. Lack of pharmacokinetic interaction as an equivalence problem. Int. J. Clin. Pharmacol. Ther. Toxicol. 29, 323-328 (1991).
97. Hollander, M. & Wolfe, D.A. Nonparametric statistical methods, Wiley, New York, (1973).
98. Endres, H.G., Henschel, L., Merkel, U., Hippius, M. & Hoffmann, A. Lack of pharmacokinetic interaction between dextromethorphan, coumarin and mephenytoin in man after simultaneous administration. Pharmazie 51, 46-51 (1996).
99. Blakey, G.E., Lockton, J.A., Perrett, J., Norwood, P., Russell, M. & Aherne, Z. et al. Pharmacokinetic and pharmacodynamic assessment of a five-probe metabolic cocktail for CYPs 1A2, 3A4, 2C9, 2D6 and 2E1. Br. J. Clin. Pharmacol. 57, 162-169 (2004).
100. Ma, J.D., Nafziger, A.N., Villano, S.A., Gaedigk, A. & Bertino, J.S. Jr Maribavir pharmacokinetics and the effects of multiple-dose maribavir on cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-acetyltransferase-2, and xanthine oxidase activities in healthy adults. Antimicrob. Agents Chemother. 50, 1130-1135 (2006).
101. Schellens, J.H., Ghabrial, H., van der Wart, H.H., Bakker, E.N., Wilkinson, G.R. & Breimer, D.D. Differential effects of quinidine on the disposition of nifedipine, sparteine, and mephenytoin in humans. Clin. Pharmacol. Ther. 50, 520-528 (1991).
102. Paolini, M., Biagi, G.L., Bauer, C. & Cantelli-Forti, G. Cocktail strategy: complications and limitations. J. Clin. Pharmacol. 33, 1011-1012 (1993).
103. Zhu, B., Ou-Yang, D.S., Chen, X.P., Huang, S.L., Tan, Z.R. & He, N. et al. Assessment of cytochrome P450 activity by a five-drug cocktail approach. Clin. Pharmacol. Ther. 70, 455-461 (2001).
104. Chen, X.P., Tan, Z.R., Huang, S.L., Huang, Z., Ou-Yang, D.S. & Zhou, H.H. Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects. Clin. Pharmacol. Ther. 73, 264-271 (2003).
105. Streetman, D.S., Bleakley, J.F., Kim, J.S., Nafziger, A.N., Leeder, J.S. & Gaedigk, A. et al. Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the Cooperstown cocktail. Clin. Pharmacol. Ther. 68, 375-383 (2000).
106. Yeh, R.F., Gaver, V.E., Patterson, K.B., Rezk, N.L., Baxter-Meheux, F. & Blake, M.J. et al. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J. Acquir. Immune Defic. Syndr. 42, 52-60 (2006).
107. Wang, Z., Gorski, J.C., Hamman, M.A., Huang, S.M., Lesko, L.J. & Hall, S.D. The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity. Clin. Pharmacol. Ther. 70, 317-326 (2001).
108. Henschel, L. & Hoffmann, A. Assessment of biotransformation capacity following oral administration of various model substances as cocktail). Z. Gastroenterol. 29, 645-649 (1991).
109. Adedoyin, A., Frye, R.F., Mauro, K. & Branch, R.A. Chloroquine modulation of specific metabolizing enzymes activities: investigation with selective five drug cocktail. Br. J. Clin. Pharmacol. 46, 215-219 (1998).
110. Adedoyin, A., Stiff, D.D., Smith, D.C., Romkes, M., Bahnson, R.C. & Day, R. et al. All-trans-retinoic acid modulation of drug-metabolizing enzyme activities: investigation with selective metabolic drug probes. Cancer Chemother. Pharmacol. 41, 133-139 (1998).
111. Branch, R.A., Adedoyin, A., Frye, R.F., Wilson, J.W. & Romkes, M. In vivo modulation of CYP enzymes by quinidine and rifampin. Clin. Pharmacol. Ther. 68, 401-411 (2000).
112. Frye, R.F., Schneider, V.M., Frye, C.S. & Feldman, A.M. Plasma levels of TNF-alpha and IL-6 are inversely related to cytochrome P450-dependent drug metabolism in patients with congestive heart failure. J. Card. Fail. 8, 315-319 (2002).
113. Bebia, Z., Buch, S.C., Wilson, J.W., Frye, R.F., Romkes, M. & Cecchetti, A. et al. Bioequivalence revisited: influence of age and sex on CYP enzymes. Clin. Pharmacol. Ther. 76, 618-627 (2004).
114. Zhang, X., Lalezari, J.P., Badley, A.D., Dorr, A., Kolis, S.J. & Kinchelow, T. et al. Assessment of drug-drug interaction potential of enfuvirtide in human immunodeficiency virus type 1-infected patients. Clin. Pharmacol. Ther. 75, 558-568 (2004).