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Probe Cocktail Studies

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Drug Interactions in Infectious Diseases: Mechanisms and Models of Drug Interactions

Part of the book series: Infectious Disease ((ID))

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Abstract

The conduct of drug interaction studies was revolutionized by the ability to evaluate more than one potential drug-drug interaction (DDI) within a single study. Cocktail studies provide a means to screen for DDIs through multiple metabolic pathways within a single study. Usually conducted in healthy volunteers, these studies use concurrent administration of probe substrates and assessment of biomarkers to simultaneously assess drug-metabolizing enzyme (DME) activities before (baseline) and during drug treatment. Evaluation of DME can be for effect of a drug on constitutive DME (i.e., inhibition, induction, or activation) or to evaluate the effect of an inhibitor, inducer, or activator on the pharmacokinetics and pharmacodynamics of the DME pathway of the drug in question. Studies should be designed with the use of safe, validated probes and published, validated cocktails. Advantages of using cocktail studies in drug development include reduced subject variability (because the same subjects are used for each phase of the study), increased efficiency, and lower costs. Potential limitations can be addressed by proper study design. Because cocktail studies assess the potential extent of DDIs, inferences for drug dosing and use may be drawn.

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References

  1. In vivo drug metabolism/drug interaction studies – study design, data analysis, and recommendations for dosing and labeling. Food and Drug Administration, Rockville, 1999

    Google Scholar 

  2. Fuhr U, Jetter A, Kirchheiner J (2007) Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the “cocktail” approach. Clin Pharmacol Ther 81(2):270–283

    Article  CAS  PubMed  Google Scholar 

  3. Zhou H, Sharma A (2016) Therapeutic protein-drug interactions: plausible mechanisms and assessment strategies. Expert Opin Drug Metab Toxicol 12(11):1–9

    Article  CAS  Google Scholar 

  4. Zhou H, Tong Z, McLeod JF (2004) “Cocktail” approaches and strategies in drug development: valuable tool or flawed science? J Clin Pharmacol 44(2):120–134

    Article  CAS  PubMed  Google Scholar 

  5. Ebner T, Ishiguro N, Taub ME (2015) The use of transporter probe drug cocktails for the assessment of transporter-based drug-drug interactions in a clinical setting-proposal of a four component transporter cocktail. J Pharm Sci 104(9):3220–3228

    Article  CAS  PubMed  Google Scholar 

  6. Ma JD, Tsunoda SM, Bertino JS Jr, Trivedi M, Beale KK, Nafziger AN (2010) Evaluation of in vivo p-glycoprotein phenotyping probes: a need for validation. Clin Pharmacokinet 49(4):223–237

    Article  CAS  PubMed  Google Scholar 

  7. Stopfer P, Giessmann T, Hohl K, Sharma A, Ishiguro N, Taub ME et al (2016) Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin. Clin Pharmacol Ther 100(3):259–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Baker SD, van Schaik RH, Rivory LP, Ten Tije AJ, Dinh K, Graveland WJ et al (2004) Factors affecting cytochrome P-450 3A activity in cancer patients. Clin Cancer Res 10(24):8341–8350

    Article  CAS  PubMed  Google Scholar 

  9. Frye RF, Zgheib NK, Matzke GR, Chaves-Gnecco D, Rabinovitz M, Shaikh OS et al (2006) Liver disease selectively modulates cytochrome P450--mediated metabolism. Clin Pharmacol Ther 80(3):235–245

    Article  CAS  PubMed  Google Scholar 

  10. Frye RF, Schneider VM, Frye CS, Feldman AM (2002) 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(5):315–319

    Article  CAS  PubMed  Google Scholar 

  11. McConn DJ, Lin YS, Mathisen TL, Blough DK, Xu Y, Hashizume T et al (2009) Reduced duodenal cytochrome P450 3A protein expression and catalytic activity in patients with cirrhosis. Clin Pharmacol Ther 85(4):387–393

    Article  CAS  PubMed  Google Scholar 

  12. Lee CM, Pohl J, Morgan ET (2009) Dual mechanisms of CYP3A protein regulation by proinflammatory cytokine stimulation in primary hepatocyte cultures. Drug Metab Dispos 37(4):865–872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jones AE, Brown KC, Werner RE, Gotzkowsky K, Gaedigk A, Blake M et al (2010) Variability in drug metabolizing enzyme activity in HIV-infected patients. Eur J Clin Pharmacol 66:475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hukkanen J, Vaisanen T, Lassila A, Piipari R, Anttila S, Pelkonen O et al (2003) Regulation of CYP3A5 by glucocorticoids and cigarette smoke in human lung-derived cells. J Pharmacol Exp Ther 304(2):745–752

    Article  CAS  PubMed  Google Scholar 

  15. He P, Court MH, Greenblatt DJ, Von Moltke LL (2005) Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Ther 77(5):373–387

    Article  CAS  PubMed  Google Scholar 

  16. Saari TI, Laine K, Neuvonen M, Neuvonen PJ, Olkkola KT (2008) Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl. Eur J Clin Pharmacol 64(1):25–30

    Article  CAS  PubMed  Google Scholar 

  17. Culm-Merdek KE, von Moltke LL, Gan L, Horan KA, Reynolds R, Harmatz JS et al (2006) Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with ritonavir. Clin Pharmacol Ther 79(3):243–254

    Article  CAS  PubMed  Google Scholar 

  18. Ngo N, Yan Z, Graf TN, Carrizosa DR, Kashuba AD, Dees EC et al (2009) Identification of a cranberry juice product that inhibits enteric CYP3A-mediated first-pass metabolism in humans. Drug Metab Dispos 37(3):514–522

    Article  CAS  PubMed  Google Scholar 

  19. Zhou SF (2008) Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab 9(4):310–322

    Article  CAS  PubMed  Google Scholar 

  20. Lammers LA, Achterbergh R, de Vries EM, van Nierop FS, Klumpen HJ, Soeters MR et al (2015) Short-term fasting alters cytochrome P450-mediated drug metabolism in humans. Drug Metab Dispos 43(6):819–828

    Article  CAS  PubMed  Google Scholar 

  21. Blake MJ, Gaedigk A, Pearce RE, Bomgaars LR, Christensen ML, Stowe C et al (2007) Ontogeny of dextromethorphan O- and N-demethylation in the first year of life. Clin Pharmacol Ther 81(4):510–516

    Article  CAS  PubMed  Google Scholar 

  22. Tracy TS, Venkataramanan R, Glover DD, Caritis SN (2005) Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A activity) during pregnancy. Am J Obstet Gynecol 192(2):633–639

    Article  CAS  PubMed  Google Scholar 

  23. Nolin TD, Appiah K, Kendrick SA, Le P, McMonagle E, Himmelfarb J (2006) Hemodialysis acutely improves hepatic CYP3A4 metabolic activity. J Am Soc Nephrol 17(9):2363–2367

    Article  CAS  PubMed  Google Scholar 

  24. Morgan ET, Goralski KB, Piquette-Miller M, Renton KW, Robertson GR, Chaluvadi MR et al (2008) Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer. Drug Metab Dispos 36(2):205–216

    Article  CAS  PubMed  Google Scholar 

  25. Bosilkovska M, Samer CF, Deglon J, Rebsamen M, Staub C, Dayer P et al (2014) Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots. Clin Pharmacol Ther 96(3):349–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zgheib NK, Frye RF, Tracy TS, Romkes M, Branch RA (2006) Validation of incorporating flurbiprofen into the Pittsburgh cocktail. Clin Pharmacol Ther 80(3):257–263

    Article  CAS  PubMed  Google Scholar 

  27. Ozdemir V, Kalowa W, Tang BK, Paterson AD, Walker SE, Endrenyi L et al (2000) Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics 10(5):373–388

    Article  CAS  PubMed  Google Scholar 

  28. Schellens JH, van der Wart JH, Brugman M, Breimer DD (1989) 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(2):638–645

    CAS  PubMed  Google Scholar 

  29. Lesko LJ, Lagishetty CV (2016) Are we getting the best return on investment from clinical drug-drug interaction studies? J Clin Pharmacol 56(5):555–558

    Article  CAS  PubMed  Google Scholar 

  30. Zhang L (2010) A regulatory perspective on the utilization of cocktail approach in assessing drug interactions. FIP Pharmaceutical Sciences World Congress – American Association of Pharmaceutical Scientists Annual meeting, New Orleans, 16 November 2010

    Google Scholar 

  31. Ryu JY, Song IS, Sunwoo YE, Shon JH, Liu KH, Cha IJ et al (2007) Development of the “Inje cocktail” for high-throughput evaluation of five human cytochrome P450 isoforms in vivo. Clin Pharmacol Ther 82(5):531–540

    Article  CAS  PubMed  Google Scholar 

  32. Rezk NL, Brown KC, Kashuba AD (2006) A simple and sensitive bioanalytical assay for simultaneous determination of omeprazole and its three major metabolites in human blood plasma using RP-HPLC after a simple liquid-liquid extraction procedure. J Chromatogr B Analyt Technol Biomed Life Sci 844(2):314–321

    Article  CAS  PubMed  Google Scholar 

  33. Liu Y, Jiao J, Zhang C, Lou J (2009) A simplified method to determine five cytochrome p450 probe drugs by HPLC in a single run. Biol Pharm Bull 32(4):717–720

    Article  CAS  PubMed  Google Scholar 

  34. CHMP Efficacy Working Party Therapeutic Subgroup on Pharmacokinetics. London: European Medicines Agency; 2009 22 January. Contract No.: EMEA/618604/2008

    Google Scholar 

  35. Drug interaction studies —study design, data analysis, implications for dosing, and labeling recommendations In: Pharmacology C (ed) US Food and Drug Administration, Silver Spring, MD, 2012, pp 1–79

    Google Scholar 

  36. Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S et al (2003) The conduct of in vitro and in vivo drug-drug interaction studies: a pharmaceutical research and manufacturers of America (PhRMA) perspective. Drug Metab Dispos 31(7):815–832

    Article  CAS  PubMed  Google Scholar 

  37. Tucker GT, Houston JB, Huang SM (2001) Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential – toward a consensus. Pharm Res 18(8):1071–1080

    Article  CAS  PubMed  Google Scholar 

  38. Huang SM, Temple R, Throckmorton DC, Lesko LJ (2007) Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin Pharmacol Ther 81(2):298–304

    Article  CAS  PubMed  Google Scholar 

  39. Bertino JS Jr, Nafziger AN (2007) Labeling of drug interactions. Is change needed? Clin Pharmacol Ther 81(Suppl):S90

    Google Scholar 

  40. Liu X, Jia L (2007) The conduct of drug metabolism studies considered good practice (I): analytical systems and in vivo studies. Curr Drug Metab 8(8):815–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bjornsson T, Callaghan J, Einolf H, Fischer V, Gan L, Grimm S et al (2003) The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J Clin Pharmacol 43:443–469

    Article  CAS  PubMed  Google Scholar 

  42. Jia L, Liu X (2007) The conduct of drug metabolism studies considered good practice (II): in vitro experiments. Curr Drug Metab 8(8):822–829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Venkatakrishnan K, von Moltke LL, Obach RS, Greenblatt DJ (2003) Drug metabolism and drug interactions: application and clinical value of in vitro models. Curr Drug Metab 4(5):423–459

    Article  CAS  PubMed  Google Scholar 

  44. Wienkers LC, Heath TG (2005) Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov 4(10):825–833

    Article  CAS  PubMed  Google Scholar 

  45. Krosser S, Neugebauer R, Dolgos H, Fluck M, Rost KL, Kovar A (2006) 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(4):277–284

    Article  PubMed  CAS  Google Scholar 

  46. Rostami-Hodjegan A, Tucker G (2004) ‘In silico’ simulations to assess the ‘in vivo’ consequences of ‘in vitro’ metabolic drug–drug interactions. Drug Discov Today Technol 1(4):441–448

    Article  CAS  PubMed  Google Scholar 

  47. Drug interaction studies-study design, data analysis, and implications for dosing and labeling. U.S. Food and Drug Administration, Rockville, 2006

    Google Scholar 

  48. Davit B, Reynolds K, Yuan R, Ajayi F, Conner D, Fadiran E et al (1999) FDA evaluations using in vitro metabolism to predict and interpret in vivo metabolic drug-drug interactions: impact on labeling. J Clin Pharmacol 39(9):899–910

    Article  CAS  PubMed  Google Scholar 

  49. Weaver RJ (2001) Assessment of drug-drug interactions: concepts and approaches. Xenobiotica 31(8-9):499–538

    Article  CAS  PubMed  Google Scholar 

  50. Lu C, Hatsis P, Berg C, Lee FW, Balani SK (2008) Prediction of pharmacokinetic drug-drug interactions using human hepatocyte suspension in plasma and cytochrome P450 phenotypic data. II. In vitro-in vivo correlation with ketoconazole. Drug Metab Dispos 36(7):1255–1260

    Article  CAS  PubMed  Google Scholar 

  51. Lu C, Miwa GT, Prakash SR, Gan LS, Balani SK (2007) A novel model for the prediction of drug-drug interactions in humans based on in vitro cytochrome p450 phenotypic data. Drug Metab Dispos 35(1):79–85

    Article  CAS  PubMed  Google Scholar 

  52. Grimm SW, Einolf HJ, Hall SD, He K, Lim HK, Ling KH et al (2009) The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the pharmaceutical research and manufacturers of America. Drug Metab Dispos 37(7):1355–1370

    Article  CAS  PubMed  Google Scholar 

  53. Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration, 2015

    Google Scholar 

  54. Table 2-1: Examples of clinical index substrates for P450-mediated metabolism (for use in index clinical DDI studies) (9/26/2016): US Food and Drug Administration; 2016 [updated 26 September 2016. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm – table2-1

  55. Watkins P (1994) Noninvasive tests of CYP3A enzymes. Pharmacogenetics 4:171–184

    Article  CAS  PubMed  Google Scholar 

  56. Frank D, Jaehde U, Fuhr U (2007) Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping. Eur J Clin Pharmacol 63(4):321–333

    Article  CAS  PubMed  Google Scholar 

  57. Borges S, Li L, Hamman MA, Jones DR, Hall SD, Gorski JC (2005) Dextromethorphan to dextrorphan urinary metabolic ratio does not reflect dextromethorphan oral clearance. Drug Metab Dispos 33(7):1052–1055

    Article  CAS  PubMed  Google Scholar 

  58. Ozdemir M, Crewe KH, Tucker GT, Rostami-Hodjegan A (2004) Assessment of in vivo CYP2D6 activity: differential sensitivity of commonly used probes to urine pH. J Clin Pharmacol 44(12):1398–1404

    Article  CAS  PubMed  Google Scholar 

  59. Labbe L, Sirois C, Pilote S, Arseneault M, Robitaille NM, Turgeon J et al (2000) Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metabolic ratios of marker substrates. Pharmacogenetics 10(5):425–438

    Article  CAS  PubMed  Google Scholar 

  60. Bioavailability and bioequivalence requirements; Abbreviated applications; Final Rule. In: Food and Drug Administration H (ed), U.S. Department of Health and Human Services, 2002, pp 77668–77675

    Google Scholar 

  61. Thummel KE, Shen DD, Podoll TD, Kunze KL, Trager WF, Bacchi CE et al (1994) Use of midazolam as a human cytochrome P450 3A probe: II. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation. J Pharmacol Exp Ther 271(1):557–566

    CAS  PubMed  Google Scholar 

  62. Thummel KE, Shen DD, Podoll TD, Kunze KL, Trager WF, Hartwell PS et al (1994) Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients. J Pharmacol Exp Ther 271(1):549–556

    CAS  PubMed  Google Scholar 

  63. Streetman DS, Kashuba AD, Bertino JS Jr, Kulawy R, Rocci ML Jr, Nafziger AN (2001) Use of midazolam urinary metabolic ratios for cytochrome P450 3A (CYP3A) phenotyping. Pharmacogenetics 11(4):349–355

    Article  CAS  PubMed  Google Scholar 

  64. Lee LS, Bertino JS Jr, Nafziger AN (2006) Limited sampling models for oral midazolam: midazolam plasma concentrations, not the ratio of 1-hydroxymidazolam to midazolam plasma concentrations, accurately predicts AUC as a biomarker of CYP3A activity. J Clin Pharmacol 46(2):229–234

    Article  CAS  PubMed  Google Scholar 

  65. Ma JD, Nafziger AN, Kashuba AD, Kim MJ, Gaedigk A, Rowland E et al (2004) Limited sampling strategy of S-warfarin concentrations, but not warfarin S/R ratios, accurately predicts S-warfarin AUC during baseline and inhibition in CYP2C9 extensive metabolizers. J Clin Pharmacol 44(6):570–576

    Article  CAS  PubMed  Google Scholar 

  66. Rogers JF, Nafziger AN, Kashuba AD, Streetman DS, Rocci ML Jr, Choo EF et al (2002) Single plasma concentrations of 1′-hydroxymidazolam or the ratio of 1′-hydroxymidazolam:midazolam do not predict midazolam clearance in healthy subjects. J Clin Pharmacol 42(10):1079–1082

    Article  CAS  PubMed  Google Scholar 

  67. Guideline on the investigation of drug interactions. In: Products CfHM, editor. CPMP/EWP/560/95/Rev. 1 Corr. 2 ed. European Medicines Agency, London, 2012, pp 1–59

    Google Scholar 

  68. Fuhr U, Rost KL (1994) Simple and reliable CYP1A2 phenotyping by the paraxanthine/caffeine ratio in plasma and in saliva. Pharmacogenetics 4(3):109–116

    Article  CAS  PubMed  Google Scholar 

  69. Johnson BM, Song IH, Adkison KK, Borland J, Fang L, Lou Y et al (2006) Evaluation of the drug interaction potential of aplaviroc, a novel human immunodeficiency virus entry inhibitor, using a modified Cooperstown 5 + 1 cocktail. J Clin Pharmacol 46(5):577–587

    Article  CAS  PubMed  Google Scholar 

  70. Sarkar MA, Jackson BJ (1994) Theophylline N-demethylations as probes for P4501A1 and P4501A2. Drug Metab Dispos 22(6):827–834

    CAS  PubMed  Google Scholar 

  71. Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ (2004) Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther 76(6):598–606

    Article  CAS  PubMed  Google Scholar 

  72. Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM et al (2000) Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 28(10):1222–1230

    CAS  PubMed  Google Scholar 

  73. Kharasch ED, Mitchell D, Coles R (2008) Stereoselective bupropion hydroxylation as an in vivo phenotypic probe for cytochrome P4502B6 (CYP2B6) activity. J Clin Pharmacol 48(4):464–474

    Article  CAS  PubMed  Google Scholar 

  74. Totah RA, Rettie AE (2005) Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance. Clin Pharmacol Ther 77(5):341–352

    Article  CAS  PubMed  Google Scholar 

  75. Niemi M, Backman JT, Neuvonen PJ (2004) Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone. Clin Pharmacol Ther 76(3):239–249

    Article  CAS  PubMed  Google Scholar 

  76. Bidstrup TB, Bjornsdottir I, Sidelmann UG, Thomsen MS, Hansen KT (2003) CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol 56(3):305–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kumar V, Wahlstrom JL, Rock DA, Warren CJ, Gorman LA, Tracy TS (2006) CYP2C9 inhibition: impact of probe selection and pharmacogenetics on in vitro inhibition profiles. Drug Metab Dispos 34(12):1966–1975

    Article  CAS  PubMed  Google Scholar 

  78. Jetter A, Kinzig-Schippers M, Skott A, Lazar A, Tomalik-Scharte D, Kirchheiner J et al (2004) Cytochrome P450 2C9 phenotyping using low-dose tolbutamide. Eur J Clin Pharmacol 60(3):165–171

    Article  CAS  PubMed  Google Scholar 

  79. Kupfer A, Preisig R (1984) Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 26(6):753–759

    Article  CAS  PubMed  Google Scholar 

  80. Xie HG, Stein CM, Kim RB, Wilkinson GR, Flockhart DA, Wood AJ (1999) Allelic, genotypic and phenotypic distributions of S-mephenytoin 4′-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 9(5):539–549

    Article  CAS  PubMed  Google Scholar 

  81. Chang M, Tybring G, Dahl ML, Gotharson E, Sagar M, Seensalu R et al (1995) Interphenotype differences in disposition and effect on gastrin levels of omeprazole – suitability of omeprazole as a probe for CYP2C19. Br J Clin Pharmacol 39(5):511–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lasker JM, Wester MR, Aramsombatdee E, Raucy JL (1998) Characterization of CYP2C19 and CYP2C9 from human liver: respective roles in microsomal tolbutamide, S-mephenytoin, and omeprazole hydroxylations. Arch Biochem Biophys 353(1):16–28

    Article  CAS  PubMed  Google Scholar 

  83. Karam WG, Goldstein JA, Lasker JM, Ghanayem BI (1996) Human CYP2C19 is a major omeprazole 5-hydroxylase, as demonstrated with recombinant cytochrome P450 enzymes. Drug Metab Dispos 24(10):1081–1087

    CAS  PubMed  Google Scholar 

  84. Miura M, Tada H, Yasui-Furukori N, Uno T, Sugawara K, Tateishi T et al (2004) Pharmacokinetic differences between the enantiomers of lansoprazole and its metabolite, 5-hydroxylansoprazole, in relation to CYP2C19 genotypes. Eur J Clin Pharmacol 60(9):623–628

    Article  CAS  PubMed  Google Scholar 

  85. Thacker DL, Modak AS, Lemler SM, Flockhart DA, Desta Z (2010) Cytochrome P450 (CYP) 2C19 specific breath test using (+)-[13C]-pantoprazole as a phenotype probe. Clin Pharmacol Ther 87(Suppl 1):S51

    Google Scholar 

  86. Desta Z, Modak A, Nguyen PD, Lemler SM, Kurogi Y, Li L et al (2009) Rapid identification of the hepatic cytochrome P450 2C19 activity using a novel and noninvasive [13C]pantoprazole breath test. J Pharmacol Exp Ther 329(1):297–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Streetman D, Bertino J Jr, Nafziger A (2000) Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 10:187–216

    Article  CAS  PubMed  Google Scholar 

  88. Spina E, Avenoso A, Campo GM, Scordo MG, Caputi AP, Perucca E (1997) Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects. Br J Clin Pharmacol 43(3):315–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Lindamood C, Ortiz S, Shaw A, Rackley R, Gorski JC (2011) Effects of commonly administered agents and genetics on nebivolol pharmacokinetics: drug-drug interaction studies. J Clin Pharmacol 51(4):575–585

    Article  CAS  PubMed  Google Scholar 

  90. Frye RF, Adedoyin A, Mauro K, Matzke GR, Branch RA (1998) Use of chlorzoxazone as an in vivo probe of cytochrome P450 2E1: choice of dose and phenotypic trait measure. J Clin Pharmacol 38(1):82–89

    Article  CAS  PubMed  Google Scholar 

  91. Mishin VM, Rosman AS, Basu P, Kessova I, Oneta CM, Lieber CS (1998) Chlorzoxazone pharmacokinetics as a marker of hepatic cytochrome P4502E1 in humans. Am J Gastroenterol 93(11):2154–2161

    Article  CAS  PubMed  Google Scholar 

  92. Tsunoda S, Velez R, von Moltke L, Greenblatt D (1999) Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo proble: effect of ketoconazole. Clin Pharmacol Ther 66:461–471

    Article  CAS  PubMed  Google Scholar 

  93. Chaobal HN, Kharasch ED (2005) Single-point sampling for assessment of constitutive, induced, and inhibited cytochrome P450 3A activity with alfentanil or midazolam. Clin Pharmacol Ther 78(5):529–539

    Article  CAS  PubMed  Google Scholar 

  94. Kharasch ED, Walker A, Hoffer C, Sheffels P (2004) Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis. Clin Pharmacol Ther 76(5):452–466

    Article  CAS  PubMed  Google Scholar 

  95. Kharasch ED, Hoffer C, Walker A, Sheffels P (2003) Disposition and miotic effects of oral alfentanil: a potential noninvasive probe for first-pass cytochrome P4503A activity. Clin Pharmacol Ther 73(3):199–208

    Article  CAS  PubMed  Google Scholar 

  96. Jalava KM, Olkkola KT, Neuvonen PJ (1997) Itraconazole greatly increases plasma concentrations and effects of felodipine. Clin Pharmacol Ther 61(4):410–415

    Article  CAS  PubMed  Google Scholar 

  97. von Moltke LL, Greenblatt DJ, Harmatz JS, Duan SX, Harrel LM, Cotreau-Bibbo MM et al (1996) Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J Pharmacol Exp Ther 276(2):370–379

    Google Scholar 

  98. Perloff MD, von Moltke LL, Court MH, Kotegawa T, Shader RI, Greenblatt DJ (2000) Midazolam and triazolam biotransformation in mouse and human liver microsomes: relative contribution of CYP3A and CYP2C isoforms. J Pharmacol Exp Ther 292(2):618–628

    CAS  PubMed  Google Scholar 

  99. Chainuvati S, Nafziger AN, Leeder JS, Gaedigk A, Kearns GL, Sellers E et al (2003) 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(5):437–447

    Article  CAS  PubMed  Google Scholar 

  100. Turpault S, Brian W, Van Horn R, Santoni A, Poitiers F, Donazzolo Y et al (2009) Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol 68(6):928–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Berthou F, Goasduff T, Lucas D, Dreano Y, Le Bot MH, Menez JF (1995) Interaction between two probes used for phenotyping cytochromes P4501A2 (caffeine) and P4502E1 (chlorzoxazone) in humans. Pharmacogenetics 5(2):72–79

    Article  CAS  PubMed  Google Scholar 

  102. Backman JT, Granfors MT, Neuvonen PJ (2006) Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine. Eur J Clin Pharmacol 62(6):451–461

    Article  CAS  PubMed  Google Scholar 

  103. Zhang L, Zhang Y, Zhao P, Huang S-M (2009) Predicting drug-drug interactions: an FDA perspective. AAPS J 11(2):300–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Backman JT, Filppula AM, Niemi M, Neuvonen PJ (2016) Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev 68(1):168–241

    Article  PubMed  Google Scholar 

  105. Niemi M, Backman JT, Juntti-Patinen L, Neuvonen M, Neuvonen PJ (2005) Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide. Br J Clin Pharmacol 60(2):208–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Daily EB, Aquilante CL (2009) Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies. Pharmacogenomics 10(9):1489–1510

    Article  CAS  PubMed  Google Scholar 

  107. Bruce MA, Hall SD, Haehner-Daniels BD, Gorski JC (2001) In vivo effect of clarithromycin on multiple cytochrome P450s. Drug Metab Dispos 29(7):1023–1028

    CAS  PubMed  Google Scholar 

  108. Yasar U, Forslund-Bergengren C, Tybring G, Dorado P, Llerena A, Sjoqvist F et al (2002) Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype. Clin Pharmacol Ther 71(1):89–98

    Article  CAS  PubMed  Google Scholar 

  109. Babaoglu MO, Yasar U, Sandberg M, Eliasson E, Dahl ML, Kayaalp SO et al (2004) CYP2C9 genetic variants and losartan oxidation in a Turkish population. Eur J Clin Pharmacol 60(5):337–342

    Article  CAS  PubMed  Google Scholar 

  110. Allabi AC, Gala JL, Horsmans Y, Babaoglu MO, Bozkurt A, Heusterspreute M et al (2004) Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911 in vivo among black Africans. Clin Pharmacol Ther 76(2):113–118

    Article  CAS  PubMed  Google Scholar 

  111. Yasar U, Eliasson E, Forslund-Bergengren C, Tybring G, Gadd M, Sjoqvist F et al (2001) The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro. Eur J Clin Pharmacol 57(10):729–735

    Article  CAS  PubMed  Google Scholar 

  112. Kumar V, Brundage RC, Oetting WS, Leppik IE, Tracy TS (2008) Differential genotype dependent inhibition of CYP2C9 in humans. Drug Metab Dispos 36(7):1242–1248

    Article  CAS  PubMed  Google Scholar 

  113. Dorado P, Berecz R, Norberto MJ, Yasar U, Dahl ML, Llerena A (2003) CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers. Eur J Clin Pharmacol 59(3):221–225

    Article  CAS  PubMed  Google Scholar 

  114. Dorado P, Cavaco I, Caceres MC, Piedade R, Ribeiro V, Llerena A (2008) Relationship between CYP2C8 genotypes and diclofenac 5-hydroxylation in healthy Spanish volunteers. Eur J Clin Pharmacol 64(10):967–970

    Article  CAS  PubMed  Google Scholar 

  115. Kirchheiner J, Meineke I, Steinbach N, Meisel C, Roots I, Brockmoller J (2003) Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans. Br J Clin Pharmacol 55(1):51–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hassan-Alin M, Andersson T, Niazi M, Rohss K (2005) A pharmacokinetic study comparing single and repeated oral doses of 20 mg and 40 mg omeprazole and its two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, in healthy subjects. Eur J Clin Pharmacol 60(11):779–784

    Article  CAS  PubMed  Google Scholar 

  117. Tybring G, Bottiger Y, Widen J, Bertilsson L (1997) Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects. Clin Pharmacol Ther 62(2):129–137

    Article  CAS  PubMed  Google Scholar 

  118. Masica AL, Mayo G, Wilkinson GR (2004) In vivo comparisons of constitutive cytochrome P450 3A activity assessed by alprazolam, triazolam, and midazolam. Clin Pharmacol Ther 76(4):341–349

    Article  CAS  PubMed  Google Scholar 

  119. Kim JS, Nafziger AN, Tsunoda SM, Choo EE, Streetman DS, Kashuba AD et al (2002) Limited sampling strategy to predict AUC of the CYP3A phenotyping probe midazolam in adults: application to various assay techniques. J Clin Pharmacol 42(4):376–382

    Article  CAS  PubMed  Google Scholar 

  120. Chung E, Nafziger AN, Kazierad DJ, Bertino JS Jr (2006) Comparison of midazolam and simvastatin as cytochrome P450 3A probes. Clin Pharmacol Ther 79(4):350–361

    Article  CAS  PubMed  Google Scholar 

  121. Kharasch ED, Thummel KE, Watkins PB (2005) CYP3A probes can quantitatively predict the in vivo kinetics of other CYP3A substrates and can accurately assess CYP3A induction and inhibition. Mol Interv 5(3):151–153

    Article  CAS  PubMed  Google Scholar 

  122. Christensen M, Andersson K, Dalen P, Mirghani RA, Muirhead GJ, Nordmark A et al (2003) The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin Pharmacol Ther 73(6):517–528

    Article  CAS  PubMed  Google Scholar 

  123. Mirghani RA, Ericsson O, Tybring G, Gustafsson LL, Bertilsson L (2003) Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man. Eur J Clin Pharmacol 59(1):23–28

    Article  CAS  PubMed  Google Scholar 

  124. Foti RS, Rock DA, Wienkers LC, Wahlstrom JL (2010) Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dispos 38(6):981–987

    Article  CAS  PubMed  Google Scholar 

  125. Mitra AK, Thummel KE, Kalhorn TF, Kharasch ED, Unadkat JD, Slattery JT (1995) Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo. Clin Pharmacol Ther 58(5):556–566

    Article  CAS  PubMed  Google Scholar 

  126. Gill HJ, Tingle MD, Park BK (1995) N-Hydroxylation of dapsone by multiple enzymes of cytochrome P450: implications for inhibition of haemotoxicity. Br J Clin Pharmacol 40(6):531–538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Gass RJ, Gal J, Fogle PW, Detmar-Hanna D, Gerber JG (1998) Neither dapsone hydroxylation nor cortisol 6beta-hydroxylation detects the inhibition of CYP3A4 by HIV-1 protease inhibitors. Eur J Clin Pharmacol 54(9-10):741–747

    Article  CAS  PubMed  Google Scholar 

  128. Frye RF, Matzke GR, Adedoyin A, Porter JA, Branch RA (1997) Validation of the five-drug “Pittsburgh cocktail” approach for assessment of selective regulation of drug-metabolizing enzymes. Clin Pharmacol Ther 62(4):365–376

    Article  CAS  PubMed  Google Scholar 

  129. Sharma A, Pilote S, Belanger PM, Arsenault M, Hamelin BA (2004) A convenient five-drug cocktail for the assessment of major drug metabolizing enzymes: a pilot study. Br J Clin Pharmacol 58(3):288–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kinirons MT, O'Shea D, Kim RB, Groopman JD, Thummel KE, Wood AJ et al (1999) Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A. Clin Pharmacol Ther 66(3):224–231

    Article  CAS  PubMed  Google Scholar 

  131. Ragueneau-Majlessi I, Boulenc X, Rauch C, Hachad H, Levy RH (2007) Quantitative correlations among CYP3A sensitive substrates and inhibitors: literature analysis. Curr Drug Metab 8(8):810–814

    Article  CAS  PubMed  Google Scholar 

  132. Zhu M, Zhao W, Jimenez H, Zhang D, Yeola S, Dai R et al (2005) Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes. Drug Metab Dispos 33(4):500–507

    Article  CAS  PubMed  Google Scholar 

  133. HY K, Ahn HJ, Seo KA, Kim H, Oh M, Bae SK et al (2008) The contributions of cytochromes P450 3A4 and 3A5 to the metabolism of the phosphodiesterase type 5 inhibitors sildenafil, udenafil, and vardenafil. Drug Metab Dispos 36(6):986–990

    Article  CAS  Google Scholar 

  134. Galteau MM, Shamsa F (2003) 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(10):713–733

    Article  CAS  PubMed  Google Scholar 

  135. Tomalik-Scharte D, Lutjohann D, Doroshyenko O, Frank D, Jetter A, Fuhr U (2009) Plasma 4beta-hydroxycholesterol: an endogenous CYP3A metric? Clin Pharmacol Ther 86(2):147–153

    Article  CAS  PubMed  Google Scholar 

  136. Kasichayanula S, Boulton DW, Luo WL, Rodrigues AD, Yang Z, Goodenough A et al (2014) Validation of 4beta-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects. Br J Clin Pharmacol 78(5):1122–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Bjorkhem-Bergman L, Backstrom T, Nylen H, Ronquist-Nii Y, Bredberg E, Andersson TB et al (2013) Comparison of endogenous 4beta-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin. Drug Metab Dispos 41(8):1488–1493

    Article  PubMed  CAS  Google Scholar 

  138. Xie HG, Wood AJ, Kim RB, Stein CM, Wilkinson GR (2004) Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 5(3):243–272

    Article  CAS  PubMed  Google Scholar 

  139. Lin YS, Dowling AL, Quigley SD, Farin FM, Zhang J, Lamba J et al (2002) Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol 62(1):162–172

    Article  CAS  PubMed  Google Scholar 

  140. Daly AK (2006) Significance of the minor cytochrome P450 3A isoforms. Clin Pharmacokinet 45(1):13–31

    Article  CAS  PubMed  Google Scholar 

  141. Lucas D, Ferrara R, Gonzalez E, Bodenez P, Albores A, Manno M et al (1999) Chlorzoxazone, a selective probe for phenotyping CYP2E1 in humans. Pharmacogenetics 9(3):377–388

    Article  CAS  PubMed  Google Scholar 

  142. Girre C, Lucas D, Hispard E, Menez C, Dally S, Menez JF (1994) Assessment of cytochrome P4502E1 induction in alcoholic patients by chlorzoxazone pharmacokinetics. Biochem Pharmacol 47(9):1503–1508

    Article  CAS  PubMed  Google Scholar 

  143. Palmer JL, Scott RJ, Gibson A, Dickins M, Pleasance S (2001) An interaction between the cytochrome P450 probe substrates chlorzoxazone (CYP2E1) and midazolam (CYP3A). Br J Clin Pharmacol 52(5):555–561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Jetter A, Kinzig M, Rodamer M, Tomalik-Scharte D, Sorgel F, Fuhr U (2009) Phenotyping of N-acetyltransferase type 2 and xanthine oxidase with caffeine: when should urine samples be collected? Eur J Clin Pharmacol 65(4):411–417

    Article  CAS  PubMed  Google Scholar 

  145. Kalow W, Tang BK (1993) The use of caffeine for enzyme assays: a critical appraisal. Clin Pharmacol Ther 53(5):503–514

    Article  CAS  PubMed  Google Scholar 

  146. Rothman N, Hayes RB, Bi W, Caporaso N, Broly F, Woosley RL et al (1993) Correlation between N-acetyltransferase activity and NAT2 genotype in Chinese males. Pharmacogenetics 3(5):250–255

    Article  CAS  PubMed  Google Scholar 

  147. O'Neil WM, Drobitch RK, MacArthur RD, Farrough MJ, Doll MA, Fretland AJ et al (2000) Acetylator phenotype and genotype in patients infected with HIV: discordance between methods for phenotype determination and genotype. Pharmacogenetics 10(2):171–182

    Article  CAS  PubMed  Google Scholar 

  148. Luo X, Li XM, ZY H, Cheng ZN (2009) Evaluation of CYP3A activity in humans using three different parameters based on endogenous cortisol metabolism. Acta Pharmacol Sin 30(9):1323–1329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Chen M, Nafziger AN, Bertino JS Jr (2006) Drug-metabolizing enzyme inhibition by ketoconazole does not reduce interindividual variability of CYP3A activity as measured by oral midazolam. Drug Metab Dispos 34(12):2079–2082

    Article  CAS  PubMed  Google Scholar 

  150. Penzak SR, Busse KH, Robertson SM, Formentini E, Alfaro RM, Davey RT Jr (2008) Limitations of using a single postdose midazolam concentration to predict CYP3A-mediated drug interactions. J Clin Pharmacol 48(6):671–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD (2001) The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 70(4):317–326

    CAS  PubMed  Google Scholar 

  152. Tomalik-Scharte D, Jetter A, Kinzig-Schippers M, Skott A, Sorgel F, Klaassen T et al (2005) Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers. Drug Metab Dispos 33(12):1859–1866

    CAS  PubMed  Google Scholar 

  153. Videau O, Delaforge M, Levi M, Thevenot E, Gal O, Becquemont L et al (2010) Biochemical and analytical development of the CIME cocktail for drug fate assessment in humans. Rapid Commun Mass Spectrom 24(16):2407–2419

    Article  CAS  PubMed  Google Scholar 

  154. Streetman DS, Bleakley JF, Kim JS, Nafziger AN, Leeder JS, Gaedigk A et al (2000) Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the “Cooperstown cocktail”. Clin Pharmacol Ther 68(4):375–383

    Article  CAS  PubMed  Google Scholar 

  155. Rendic S (2002) Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev 34(1-2):83–448

    Article  CAS  PubMed  Google Scholar 

  156. Shelepova T, Nafziger AN, Victory J, Kashuba AD, Rowland E, Zhang Y et al (2005) Effect of a triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated Cooperstown 5+1 cocktail. J Clin Pharmacol 45(12):1413–1421

    Article  CAS  PubMed  Google Scholar 

  157. Furman KD, Grimm DR, Mueller T, Holley-Shanks RR, Bertz RJ, Williams LA et al (2004) Impact of CYP2D6 intermediate metabolizer alleles on single-dose desipramine pharmacokinetics. Pharmacogenetics 14(5):279–284

    Article  CAS  PubMed  Google Scholar 

  158. Kim MJ, Bertino JS Jr, Gaedigk A, Zhang Y, Sellers EM, Nafziger AN (2002) Effect of sex and menstrual cycle phase on cytochrome P450 2C19 activity with omeprazole used as a biomarker. Clin Pharmacol Ther 72(2):192–199

    Article  CAS  PubMed  Google Scholar 

  159. Bromley CM, Close S, Cohen N, Favis R, Fijal B, Gheyas F et al (2009) Designing pharmacogenetic projects in industry: practical design perspectives from the Industry Pharmacogenomics Working Group. Pharmacogenomics J 9(1):14–22

    Article  CAS  PubMed  Google Scholar 

  160. Williams JA, Johnson K, Paulauskis J, Cook J (2006) So many studies, too few subjects: establishing functional relevance of genetic polymorphisms on pharmacokinetics. J Clin Pharmacol 46(3):258–264

    Article  CAS  PubMed  Google Scholar 

  161. Eap CB, Lessard E, Baumann P, Brawand-Amey M, Yessine MA, O'Hara G et al (2003) Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans. Pharmacogenetics 13(1):39–47

    Article  CAS  PubMed  Google Scholar 

  162. Kirchheiner J, Schmidt H, Tzvetkov M, Keulen JT, Lotsch J, Roots I et al (2007) Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J 7(4):257–265

    Article  CAS  PubMed  Google Scholar 

  163. Inui N, Akamatsu T, Uchida S, Tanaka S, Namiki N, Karayama M et al (2013) Chronological effects of rifampicin discontinuation on cytochrome P450 activity in healthy Japanese volunteers, using the cocktail method. Clin Pharmacol Ther 94(6):702–708

    Article  CAS  PubMed  Google Scholar 

  164. De Bock L, Boussery K, Colin P, De Smet J, T'Jollyn H, Van Bocxlaer J (2012) Development and validation of a fast and sensitive UPLC-MS/MS method for the quantification of six probe metabolites for the in vitro determination of cytochrome P450 activity. Talanta 89:209–216

    Article  PubMed  CAS  Google Scholar 

  165. Scott RJ, Palmer J, Lewis IA, Pleasance S (1999) 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(23):2305–2319

    Article  CAS  PubMed  Google Scholar 

  166. Statistical approaches to establishing bioequivalence. U.S. Department of Health and Human Services, Food and Drug Administration, Rockville, 2001

    Google Scholar 

  167. Group Mr. Drug interaction guideline for drug development and labeling recommendations (draft for public comment). Japan: Ministry of Health, Labour and Welfare, 2014, pp 75–76

    Google Scholar 

  168. Lin YS, Lockwood GF, Graham MA, Brian WR, Loi CM, Dobrinska MR et al (2001) In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration. Pharmacogenetics 11(9):781–791

    Article  CAS  PubMed  Google Scholar 

  169. Watkins PB, Wrighton SA, Maurel P, Schuetz EG, Mendez-Picon G, Parker GA et al (1985) Identification of an inducible form of cytochrome P-450 in human liver. Proc Natl Acad Sci U S A 82(18):6310–6314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Kronbach T, Fischer V, Meyer UA (1988) Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs. Clin Pharmacol Ther 43(6):630–635

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Bertino Consulting, Schenectady, NY, USA

    Anne N. Nafziger & Joseph S. Bertino Jr

  2. School of Pharmacy & Pharmaceutical Sciences, Department of Pharmacy Practice, University at Buffalo, State University of New York, Buffalo, NY, USA

    Anne N. Nafziger

  3. College of Physicians & Surgeons, Columbia University, New York, NY, USA

    Joseph S. Bertino Jr

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Correspondence to Anne N. Nafziger .

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Editors and Affiliations

  1. College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA

    Manjunath P. Pai

  2. Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, USA

    Jennifer J. Kiser

  3. Division of Pharmacy Practice and Administration, UMKC School of Pharmacy at MSU, Springfield, Missouri, USA

    Paul O. Gubbins

  4. College of Pharmacy and Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

    Keith A. Rodvold

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Nafziger, A.N., Bertino, J.S. (2018). Probe Cocktail Studies. In: Pai, M., Kiser, J., Gubbins, P., Rodvold, K. (eds) Drug Interactions in Infectious Diseases: Mechanisms and Models of Drug Interactions. Infectious Disease. Humana Press, Cham. https://doi.org/10.1007/978-3-319-72422-5_8

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