Cytochrome P450 2B6: function, genetics, and clinical relevance

References

1. Hoffman SM, Nelson DR, Keeney DS. Organization, structure and evolution of the CYP2 gene cluster on human chromosome 19. Pharmacogenetics 2001;11:687–98.10.1097/00008571-200111000-00007Search in Google Scholar PubMed

2. Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 2004;14:1–18.10.1097/00008571-200401000-00001Search in Google Scholar PubMed

3. Gervot L, Rochat B, Gautier JC, Bohnenstengel F, Kroemer H, de Berardinis V, et al. Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics 1999;9:295–306.10.1097/00008571-199906000-00004Search in Google Scholar

4. Stresser DM, Kupfer D. Monospecific antipeptide antibody to cytochrome P-450 2B6. Drug Metab Dispos 1999;27:517–25.Search in Google Scholar

5. Rostami-Hodjegan A, Tucker GT. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Discov 2007;6:140–8.10.1038/nrd2173Search in Google Scholar PubMed

6. Hofmann MH, Blievernicht JK, Klein K, Saussele T, Schaeffeler E, Schwab M, et al. Aberrant splicing caused by single nucleotide polymorphism c.516G>T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CYP2B6 in liver. J Pharmacol Exp Ther 2008;325:284–92.10.1124/jpet.107.133306Search in Google Scholar PubMed

7. Lamba V, Lamba J, Yasuda K, Strom S, Davila J, Hancock ML, et al. Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J Pharmacol Exp Ther 2003;307:906–22.10.1124/jpet.103.054866Search in Google Scholar PubMed

8. Croom EL, Stevens JC, Hines RN, Wallace AD, Hodgson E. Human hepatic CYP2B6 developmental expression: the impact of age and genotype. Biochem Pharmacol 2009;78:184–90.10.1016/j.bcp.2009.03.029Search in Google Scholar PubMed

9. Yang X, Zhang B, Molony C, Chudin E, Hao K, Zhu J, et al. Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res 2010;20:1020–36.10.1101/gr.103341.109Search in Google Scholar PubMed PubMed Central

10. Saitoh A, Fletcher CV, Brundage R, Alvero C, Fenton T, Hsia K, et al. Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism. J Acquir Immune Defic Syndr 2007;45:280–5.10.1097/QAI.0b013e318040b29eSearch in Google Scholar PubMed

11. Ding X, Kaminsky LS. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol 2003;43:149–73.10.1146/annurev.pharmtox.43.100901.140251Search in Google Scholar PubMed

12. Yengi LG, Xiang Q, Pan J, Scatina J, Kao J, Ball SE, et al. Quantitation of cytochrome P450 mRNA levels in human skin. Anal Biochem 2003;316:103–10.10.1016/S0003-2697(03)00042-3Search in Google Scholar

13. Lee AM, Miksys S, Palmour R, Tyndale RF. CYP2B6 is expressed in African Green monkey brain and is induced by chronic nicotine treatment. Neuropharmacology 2006;50:441–50.10.1016/j.neuropharm.2005.10.003Search in Google Scholar

14. Miksys S, Tyndale RF. The unique regulation of brain cytochrome P450 2 (CYP2) family enzymes by drugs and genetics. Drug Metab Rev 2004;36:313–3310.1081/DMR-120034149Search in Google Scholar

15. Gay SC, Shah MB, Talakad JC, Maekawa K, Roberts AG, Wilderman PR, et al. Crystal structure of a cytochrome P450 2B6 genetic variant in complex with the inhibitor 4-(4-chlorophenyl)imidazole at 2.0-Å resolution. Mol Pharmacol 2010;77: 529–38.10.1124/mol.109.062570Search in Google Scholar

16. Shah MB, Pascual J, Zhang Q, Stout CD, Halpert JR. Structures of cytochrome P450 2B6 bound to 4-benzylpyridine and 4-(4-nitrobenzyl)pyridine: insight into inhibitor binding and rearrangement of active site side chains. Mol Pharmacol 2011;80:1047–55.10.1124/mol.111.074427Search in Google Scholar

17. Lewis DF, Lake BG, Dickins M, Eddershaw PJ, Tarbit MH, Goldfarb PS. Molecular modelling of CYP2B6, the human CYP2B isoform, by homology with the substrate-bound CYP102 crystal structure: evaluation of CYP2B6 substrate characteristics, the cytochrome b5 binding site and comparisons with CYP2B1 and CYP2B4. Xenobiotica 1999;29:361–93.10.1080/004982599238560Search in Google Scholar

18. Lewis DF, Lake BG, Dickins M. Substrates of human cytochromes P450 from families CYP1 and CYP2: analysis of enzyme selectivity and metabolism. Drug Metabol Drug Interact 2004;20:111–42.10.1515/DMDI.2004.20.3.111Search in Google Scholar

19. Turpeinen M, Raunio H, Pelkonen O. The functional role of CYP2B6 in human drug metabolism: substrates and inhibitors in vitro, in vivo and in silico. Curr Drug Metab 2006;7:705–14.10.2174/138920006778520633Search in Google Scholar

20. Niwa T, Sato R, Yabusaki Y, Ishibashi F, Katagiri M. Contribution of human hepatic cytochrome P450s and steroidogenic CYP17 to the N-demethylation of aminopyrine. Xenobiotica 1999;29:187–93.10.1080/004982599238731Search in Google Scholar

21. Engel G, Hofmann U, Heidemann H, Cosme J, Eichelbaum M. Antipyrine as a probe for human oxidative drug metabolism: identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation. Clin Pharmacol Ther 1996;59:613–23.10.1016/S0009-9236(96)90001-6Search in Google Scholar

22. Svensson US, Ashton M. Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin. Br J Clin Pharmacol 1999;48:528–35.10.1046/j.1365-2125.1999.00044.xSearch in Google Scholar

23. Asimus S, Ashton M. Artemisinin–a possible CYP2B6 probe substrate? Biopharm Drug Dispos 2009;30:265–75.10.1002/bdd.665Search in Google Scholar

24. Hesse LM, Venkatakrishnan K, Court MH, von Moltke LL, Duan SX, Shader RI, et al. CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos 2000;28:1176–83.Search in Google Scholar

25. Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM, et al. Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 2000;28:1222–30.Search in Google Scholar

26. Giraud C, Tran A, Rey E, Vincent J, Tréluyer JM, Pons G. In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19. Drug Metab Dispos 2004;32:1279–86.10.1124/dmd.32.11.1279Search in Google Scholar

27. Roy P, Yu LJ, Crespi CL, Waxman DJ. Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 1999;27:655–66.Search in Google Scholar

28. Huang Z, Roy P, Waxman DJ. Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol 2000;59:961–72.10.1016/S0006-2952(99)00410-4Search in Google Scholar

29. Hall M, Persiani S, Cheung YL, Matthews A, Cybulski ZR, Holding JD, et al. Interaction of dexloxiglumide, a cholecystokinin type-1 receptor antagonist, with human cytochromes P450. Biopharm Drug Dispos 2004;25:163–76.10.1002/bdd.397Search in Google Scholar

30. Ono S, Hatanaka T, Miyazawa S, Tsutsui M, Aoyama T, Gonzalez FJ, et al. Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6, 2C19 and the 3A subfamily. Xenobiotica 1996;26:1155–66.10.3109/00498259609046742Search in Google Scholar

31. Bort R, Macé K, Boobis A, Gómez-Lechón MJ, Pfeifer A, Castell J. Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways. Biochem Pharmacol 1999;58: 787–96.10.1016/S0006-2952(99)00167-7Search in Google Scholar

32. Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 2003;306:287–300.10.1124/jpet.103.049601Search in Google Scholar PubMed

33. Kraemer T, Pflugmann T, Bossmann M, Kneller NM, Peters FT, Paul LD, et al. Fenproporex N-dealkylation to amphetamine–enantioselective in vitro studies in human liver microsomes as well as enantioselective in vivo studies in Wistar and Dark Agouti rats. Biochem Pharmacol 2004;68:947–57.10.1016/j.bcp.2004.05.009Search in Google Scholar PubMed

34. von Moltke LL, Greenblatt DJ, Duan SX, Schmider J, Wright CE, Harmatz JS, et al. Human cytochromes mediating N-demethylation of fluoxetine in vitro. Psychopharmacology (Berl) 1997;132:402–7.10.1007/s002130050362Search in Google Scholar PubMed

35. Margolis JM, O’Donnell JP, Mankowski DC, Ekins S, Obach RS. (R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes. Drug Metab Dispos 2000;28: 1187–91.Search in Google Scholar

36. Yanagihara Y, Kariya S, Ohtani M, Uchino K, Aoyama T, Yamamura Y, et al. Involvement of CYP2B6 in N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 2001;29:887–90.Search in Google Scholar

37. Hijazi Y, Boulieu R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 2002;30:853–8.10.1124/dmd.30.7.853Search in Google Scholar

38. Ekins S, Bravi G, Ring BJ, Gillespie TA, Gillespie JS, Vandenbranden M, et al. Three-dimensional quantitative structure activity relationship analyses of substrates for CYP2B6. J Pharmacol Exp Ther 1999;288:21–9.Search in Google Scholar

39. Imaoka S, Yamada T, Hiroi T, Hayashi K, Sakaki T, Yabusaki Y, et al. Multiple forms of human P450 expressed in Saccharomyces cerevisiae. Systematic characterization and comparison with those of the rat. Biochem Pharmacol 1996;51:1041–50.10.1016/0006-2952(96)00052-4Search in Google Scholar

40. Wang JS, Backman JT, Taavitsainen P, Neuvonen PJ, Kivistö KT. Involvement of CYP1A2 and CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans. Drug Metab Dispos 2000;28:959–65.Search in Google Scholar

41. Kim KA, Chung J, Jung DH, Park JY. Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol 2004;60:575–81.10.1007/s00228-004-0815-3Search in Google Scholar PubMed

42. Foster DJ, Somogyi AA, Bochner F. Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4. Br J Clin Pharmacol 1999;47:403–12.10.1046/j.1365-2125.1999.00921.xSearch in Google Scholar PubMed PubMed Central

43. Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality 2004;16:36–44.10.1002/chir.10303Search in Google Scholar PubMed

44. Totah RA, Sheffels P, Roberts T, Whittington D, Thummel K, Kharasch ED. Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology 2008;108:363–74.10.1097/ALN.0b013e3181642938Search in Google Scholar PubMed

45. Kharasch ED, Mitchell D, Coles R, Blanco R. Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob Agents Chemother 2008;52:1663–9.10.1128/AAC.01600-07Search in Google Scholar PubMed PubMed Central

46. Erickson DA, Mather G, Trager WF, Levy RH, Keirns JJ. Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos 1999;27:1488–95.Search in Google Scholar

47. Yamanaka H, Nakajima M, Katoh M, Kanoh A, Tamura O, Ishibashi H, et al. Trans-3’-hydroxycotinine O- and N-glucuronidations in human liver microsomes. Drug Metab Dispos 2005;33:23–30.10.1124/dmd.104.001701Search in Google Scholar PubMed

48. Ramírez J, Innocenti F, Schuetz EG, Flockhart DA, Relling MV, Santucci R, et al. CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes. Drug Metab Dispos 2004;32:930–6.Search in Google Scholar

49. Stevens JC, White RB, Hsu SH, Martinet M. Human liver CYP2B6-catalyzed hydroxylation of RP 73401. J Pharmacol Exp Ther 1997;282:1389–95.Search in Google Scholar

50. Oda Y, Hamaoka N, Hiroi T, Imaoka S, Hase I, Tanaka K, et al. Involvement of human liver cytochrome P4502B6 in the metabolism of propofol. Br J Clin Pharmacol 2001;51:281–5.10.1046/j.1365-2125.2001.00344.xSearch in Google Scholar PubMed PubMed Central

51. Court MH, Duan SX, Hesse LM, Venkatakrishnan K, Greenblatt DJ. Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Anesthesiology 2001;94:110–9.10.1097/00000542-200101000-00021Search in Google Scholar PubMed

52. Oda Y, Furuichi K, Tanaka K, Hiroi T, Imaoka S, Asada A, et al. Metabolism of a new local anesthetic, ropivacaine, by human hepatic cytochrome P450. Anesthesiology 1995;82:214–20.10.1097/00000542-199501000-00026Search in Google Scholar PubMed

53. Hidestrand M, Oscarson M, Salonen JS, Nyman L, Pelkonen O, Turpeinen M, et al. CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson’s disease, as revealed from experiments with recombinant enzymes. Drug Metab Dispos 2001;29:1480–4.Search in Google Scholar

54. Salonen JS, Nyman L, Boobis AR, Edwards RJ, Watts P, Lake BG, et al. Comparative studies on the cytochrome p450-associated metabolism and interaction potential of selegiline between human liver-derived in vitro systems. Drug Metab Dispos 2003;31:1093–102.10.1124/dmd.31.9.1093Search in Google Scholar PubMed

55. Kobayashi K, Ishizuka T, Shimada N, Yoshimura Y, Kamijima K, Chiba K. Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metab Dispos 1999a;27:763–6.Search in Google Scholar

56. Ko JW, Desta Z, Flockhart DA. Human N-demethylation of (S)-mephenytoin by cytochrome P450s 2C9 and 2B6. Drug Metab Dispos 1998;26:775–8.Search in Google Scholar

57. Heyn H, White RB, Stevens JC. Catalytic role of cytochrome P4502B6 in the N-demethylation of S-mephenytoin. Drug Metab Dispos 1996;24:948–54.Search in Google Scholar

58. Kobayashi K, Abe S, Nakajima M, Shimada N, Tani M, Chiba K, et al. Role of human CYP2B6 in S-mephobarbital N-demethylation. Drug Metab Dispos 1999b;27:1429–33.Search in Google Scholar

59. Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, et al. The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol 2002;54:157–67.10.1046/j.1365-2125.2002.01614.xSearch in Google Scholar PubMed PubMed Central

60. Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004;310:1062–75.10.1124/jpet.104.065607Search in Google Scholar PubMed

61. Ekins S, Vandenbranden M, Ring BJ, Gillespie JS, Yang TJ, Gelboin HV, et al. Further characterization of the expression in liver and catalytic activity of CYP2B6. J Pharmacol Exp Ther 1998;286:1253–9.Search in Google Scholar

62. Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, et al. Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 2001;29:1146–55.Search in Google Scholar

63. Busse D, Cosme J, Beaune P, Kroemer HK, Eichelbaum M. Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol 1995;353:116–21.10.1007/BF00168924Search in Google Scholar PubMed

64. Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 2008;392:1093–108.10.1007/s00216-008-2291-6Search in Google Scholar PubMed

65. European Medicines Agency, Committee for Human Medicinal Products (CHMP). Guideline on the investigation of drug interactions, CPMP/EWP/560/95. Available at: http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf. Accessed July 2012.Search in Google Scholar

66. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Draft guidance: Drug interaction studies – study design, data analysis, implications for dosing, and labeling recommendations. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf. Accessed July 2012.Search in Google Scholar

67. Laizure SC, DeVane CL, Stewart JT, Dommisse CS, Lai AA. Pharmacokinetics of bupropion and its major basic metabolites in normal subjects after a single dose. Clin Pharmacol Ther 1985;38:586–9.10.1038/clpt.1985.228Search in Google Scholar PubMed

68. Faucette SR, Hawke RL, Shord SS, Lecluyse EL, Lindley CM. Evaluation of the contribution of cytochrome P450 3A4 to human liver microsomal bupropion hydroxylation. Drug Metab Dispos 2001;29:1123–9.Search in Google Scholar

69. Turpeinen M, Uusitalo J, Jalonen J, Pelkonen O. Multiple P450 substrates in a single run: rapid and comprehensive in vitro interaction assay. Eur J Pharm Sci 2005;24:123–32.10.1016/j.ejps.2004.10.006Search in Google Scholar PubMed

70. Borges V, Yang E, Dunn J, Henion J. High-throughput liquid chromatography-tandem mass spectrometry determination of bupropion and its metabolites in human, mouse and rat plasma using a monolithic column. J Chromatogr B Analyt Technol Biomed Life Sci 2004;804:277–87.10.1016/j.jchromb.2004.01.024Search in Google Scholar PubMed

71. Jefferson JW, Pradko JF, Muir KT. Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations. Clin Ther 2005;27:1685–95.10.1016/j.clinthera.2005.11.011Search in Google Scholar PubMed

72. Mutlib AE, Chen H, Nemeth GA, Markwalder JA, Seitz SP, Gan LS, et al. Identification and characterization of efavirenz metabolites by liquid chromatography/mass spectrometry and high field NMR: species differences in the metabolism of efavirenz. Drug Metab Dispos 1999;27:1319–33.Search in Google Scholar

73. Desta Z, Saussele T, Ward B, Blievernicht J, Li L, Klein K, et al. Impact of CYP2B6 polymorphism on hepatic efavirenz metabolism in vitro. Pharmacogenomics 2007;8:547–58.10.2217/14622416.8.6.547Search in Google Scholar PubMed

74. Hodgson E, Rose RL. The importance of cytochrome P450 2B6 in the human metabolism of environmental chemicals. Pharmacol Ther 2007;113:420–8.10.1016/j.pharmthera.2006.10.002Search in Google Scholar PubMed

75. Crane AL, Klein K, Zanger UM, Olson JR. Effect of CYP2B6*6 and CYP2C19*2 genotype on chlorpyrifos metabolism. Toxicology 2012;293:115–22.10.1016/j.tox.2012.01.006Search in Google Scholar PubMed PubMed Central

76. Abass K, Turpeinen M, Rautio A, Hakkola J, Pelkonen O. Metabolism of pesticides by human cytochrome P450 enzymes in vitro – a survey. In: Perveen F, editor. Insecticides – advances in integrated pest management. InTech, 2012.10.5772/28088Search in Google Scholar

77. Smith GB, Bend JR, Bedard LL, Reid KR, Petsikas D, Massey TE. Biotransformation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in peripheral human lung microsomes. Drug Metab Dispos 2003;31:1134–41.10.1124/dmd.31.9.1134Search in Google Scholar PubMed

78. Code EL, Crespi CL, Penman BW, Gonzalez FJ, Chang TK, Waxman DJ. Human cytochrome P4502B6: interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metab Dispos 1997;25:985–93.Search in Google Scholar

79. Rae JM, Soukhova NV, Flockhart DA, Desta Z. Triethylenethiophosphoramide is a specific inhibitor of cytochrome P450 2B6: implications for cyclophosphamide metabolism. Drug Metab Dispos 2002;30:525–30.10.1124/dmd.30.5.525Search in Google Scholar PubMed

80. Harleton E, Webster M, Bumpus NN, Kent UM, Rae JM, Hollenberg PF. Metabolism of N,N’,N”-triethylenethiophosphoramide by CYP2B1 and CYP2B6 results in the inactivation of both isoforms by two distinct mechanisms. J Pharmacol Exp Ther 2004;310:1011–9.10.1124/jpet.104.069112Search in Google Scholar PubMed

81. Richter T, Schwab M, Eichelbaum M, Zanger UM. Inhibition of human CYP2B6 by N,N’,N”-triethylenethiophosphoramide is irreversible and mechanism-based. Biochem Pharmacol 2005;69:517–24.10.1016/j.bcp.2004.10.008Search in Google Scholar PubMed

82. Turpeinen M, Nieminen R, Juntunen T, Taavitsainen P, Raunio H, Pelkonen O. Selective inhibition of CYP2B6-catalyzed bupropion hydroxylation in human liver microsomes in vitro. Drug Metab Dispos 2004;32:626–31.10.1124/dmd.32.6.626Search in Google Scholar PubMed

83. Richter T, Mürdter TE, Heinkele G, Pleiss J, Tatzel S, Schwab M, et al. Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J Pharmacol Exp Ther 2004;308:189–97.10.1124/jpet.103.056127Search in Google Scholar PubMed

84. Turpeinen M, Tolonen A, Uusitalo J, Jalonen J, Pelkonen O, Laine K. Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clin Pharmacol Ther 2005;77:553–9.10.1016/j.clpt.2005.02.010Search in Google Scholar

85. Kent UM, Mills DE, Rajnarayanan RV, Alworth WL, Hollenberg PF. Effect of 17-α-ethynylestradiol on activities of cytochrome P450 2B (P450 2B) enzymes: characterization of inactivation of P450s 2B1 and 2B6 and identification of metabolites. J Pharmacol Exp Ther 2002;300:549–58.10.1124/jpet.300.2.549Search in Google Scholar

86. Palovaara S, Pelkonen O, Uusitalo J, Lundgren S, Laine K. Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation. Clin Pharmacol Ther 2003;74: 326–33.10.1016/S0009-9236(03)00202-9Search in Google Scholar

87. Jeong S, Nguyen PD, Desta Z. Comprehensive in vitro analysis of voriconazole inhibition of eight cytochrome P450 (CYP) enzymes: major effect on CYPs 2B6, 2C9, 2C19, and 3A. Antimicrob Agents Chemother 2009;53:541–51.10.1128/AAC.01123-08Search in Google Scholar PubMed PubMed Central

88. Chun J, Kent UM, Moss RM, Sayre LM, Hollenberg PF. Mechanism-based inactivation of cytochromes P450 2B1 and P450 2B6 by 2-phenyl-2-(1-piperidinyl)propane. Drug Metab Dispos 2000;28:905–11.Search in Google Scholar

89. Walsky RL, Obach RS. A comparison of 2-phenyl-2-(1-piperidinyl)propane (ppp), 1,1’,1”-phosphinothioylidynetrisaziridine (thioTEPA), clopidogrel, and ticlopidine as selective inactivators of human cytochrome P450 2B6. Drug Metab Dispos 2007;35:2053–9.10.1124/dmd.107.015883Search in Google Scholar PubMed

90. Korhonen LE, Turpeinen M, Rahnasto M, Wittekindt C, Poso A, Pelkonen O, et al. New potent and selective cytochrome P450 2B6 (CYP2B6) inhibitors based on three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. Br J Pharmacol 2007;150:932–42.10.1038/sj.bjp.0707173Search in Google Scholar PubMed PubMed Central

91. Huitema AD, Kerbusch T, Tibben MM, Rodenhuis S, Beijnen JH. Reduction of cyclophosphamide bioactivation by thioTEPA: critical sequence-dependency in high-dose chemotherapy regimens. Cancer Chemother Pharmacol 2000;46:119–27.10.1007/s002800000132Search in Google Scholar PubMed

92. Ha-Duong NT, Dijols S, Macherey AC, Goldstein JA, Dansette PM, Mansuy D. Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19. Biochemistry 2001;40: 12112–22.10.1021/bi010254cSearch in Google Scholar PubMed

93. Jiang F, Desta Z, Shon JH, Yeo CW, Kim HS, Liu KH, et al. Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl-metabolites: exploration of a novel CYP2B6 phenotyping index. Br J Clin Pharmacol 2012, in press.10.1111/j.1365-2125.2012.04314.xSearch in Google Scholar PubMed PubMed Central

94. Liu P, Foster G, LaBadie RR, Gutierrez MJ, Sharma A. Pharmacokinetic interaction between voriconazole and efavirenz at steady state in healthy male subjects. J Clin Pharmacol 2008;48:73–84.10.1177/0091270007309703Search in Google Scholar PubMed

95. Peltoniemi MA, Saari TI, Hagelberg NM, Reponen P, Turpeinen M, Laine K, et al. Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. Clin Pharmacol Ther 2011;90:296–302.10.1038/clpt.2011.140Search in Google Scholar

96. Remmer H, Merker HJ. Drug-induced changes in the liver endoplasmic reticulum: association with drug-metabolizing enzymes. Science 1963;142:1657–8.10.1126/science.142.3600.1657Search in Google Scholar

97. Sueyoshi T, Kawamoto T, Zelko I, Honkakoski P, Negishi M. The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J Biol Chem 1999;274:6043–6.10.1074/jbc.274.10.6043Search in Google Scholar

98. Faucette SR, Zhang TC, Moore R, Sueyoshi T, Omiecinski CJ, LeCluyse EL, et al. Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Exp Ther 2007;320:72–80.10.1124/jpet.106.112136Search in Google Scholar

99. Pelkonen O, Turpeinen M, Hakkola J, Honkakoski P, Hukkanen J, Raunio H. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol 2008;82:667–715.10.1007/s00204-008-0332-8Search in Google Scholar

100. Simonsson US, Jansson B, Hai TN, Huong DX, Tybring G, Ashton M. Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9. Clin Pharmacol Ther 2003;74:32–43.10.1016/S0009-9236(03)00092-4Search in Google Scholar

101. Burk O, Arnold KA, Nussler AK, Schaeffeler E, Efimova E, Avery BA, et al. Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 2005;67:1954–65.10.1124/mol.104.009019Search in Google Scholar PubMed

102. Lindley C, Hamilton G, McCune JS, Faucette S, Shord SS, Hawke RL, et al. The effect of cyclophosphamide with and without dexamethasone on cytochrome P450 3A4 and 2B6 in human hepatocytes. Drug Metab Dispos 2002;30:814–22.10.1124/dmd.30.7.814Search in Google Scholar PubMed

103. Saussele T, Burk O, Blievernicht JK, Klein K, Nussler A, Nussler N, et al. Selective induction of human hepatic cytochromes P450 2B6 and 3A4 by metamizole. Clin Pharmacol Ther 2007;82:265–74.10.1038/sj.clpt.6100138Search in Google Scholar PubMed

104. Qin WJ, Zhang W, Liu ZQ, Chen XP, Tan ZR, Hu DL, et al. Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men. Br J Clin Pharmacol 2012, in press.10.1111/j.1365-2125.2012.04304.xSearch in Google Scholar PubMed PubMed Central

105. Goodwin B, Moore LB, Stoltz CM, McKee DD, Kliewer SA. Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Mol Pharmacol 2001;60:427–31.Search in Google Scholar

106. Honkakoski P, Zelko I, Sueyoshi T, Negishi M. The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 1998;18:5652–8.10.1128/MCB.18.10.5652Search in Google Scholar PubMed PubMed Central

107. Slattery JT, Kalhorn TF, McDonald GB, Lambert K, Buckner CD, Bensinger WI, et al. Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients. J Clin Oncol 1996;14:1484–94.10.1200/JCO.1996.14.5.1484Search in Google Scholar PubMed

108. Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, et al. Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos 2004;32:348–58.10.1124/dmd.32.3.348Search in Google Scholar PubMed

109. Wang H, Faucette S, Moore R, Sueyoshi T, Negishi M, LeCluyse E. Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. J Biol Chem 2004;279:29295–301.10.1074/jbc.M400580200Search in Google Scholar PubMed

110. Loboz KK, Gross AS, Williams KM, Liauw WS, Day RO, Blievernicht JK, et al. Cytochrome P450 2B6 activity as measured by bupropion hydroxylation: effect of induction by rifampin and ethnicity. Clin Pharmacol Ther 2006;80:75–84.10.1016/j.clpt.2006.03.010Search in Google Scholar PubMed

111. Feidt DM, Klein K, Hofmann U, Riedmaier S, Knobeloch D, Thasler WE, et al. Profiling induction of cytochrome p450 enzyme activity by statins using a new liquid chromatography-tandem mass spectrometry cocktail assay in human hepatocytes. Drug Metab Dispos 2010;38:1589–97.10.1124/dmd.110.033886Search in Google Scholar PubMed

112. Kharasch ED, Hankins DC, Thummel KE. Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology 1995;82:689–99.10.1097/00000542-199503000-00011Search in Google Scholar PubMed

113. Oscarson M, Zanger UM, Rifki OF, Klein K, Eichelbaum M, Meyer UA. Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther 2006;80:440–56.10.1016/j.clpt.2006.08.013Search in Google Scholar PubMed

114. Lang T, Klein K, Fischer J, Nüssler AK, Neuhaus P, Hofmann U, et al. Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 2001;11:399–415. Erratum in: Pharmacogenetics 2001;11:643.Search in Google Scholar

115. Lang T, Klein K, Richter T, Zibat A, Kerb R, Eichelbaum M, et al. Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles. J Pharmacol Exp Ther 2004;311:34–43.10.1124/jpet.104.068973Search in Google Scholar PubMed

116. Hesse LM, He P, Krishnaswamy S, Hao Q, Hogan K, von Moltke LL, et al. Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Pharmacogenetics 2004;14:225–38.10.1097/00008571-200404000-00002Search in Google Scholar PubMed

117. Klein K, Lang T, Saussele T, Barbosa-Sicard E, Schunck WH, Eichelbaum M, et al. Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz. Pharmacogenet Genomics 2005;15:861–73.10.1097/01213011-200512000-00004Search in Google Scholar PubMed

118. Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, Schwab M. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics 2007;8:743–59.10.2217/14622416.8.7.743Search in Google Scholar PubMed

119. Telenti A, Zanger UM. Pharmacogenetics of anti-HIV drugs. Annu Rev Pharmacol Toxicol 2008;48:227–56.10.1146/annurev.pharmtox.48.113006.094753Search in Google Scholar PubMed

120. Zhang H, Sridar C, Kenaan C, Amunugama H, Ballou DP, Hollenberg PF. Polymorphic variants of cytochrome P450 2B6 (CYP2B6.4-CYP2B6.9) exhibit altered rates of metabolism for bupropion and efavirenz: a charge-reversal mutation in the K139E variant (CYP2B6.8) impairs formation of a functional cytochrome p450-reductase complex. J Pharmacol Exp Ther 2011;338:803–9.10.1124/jpet.111.183111Search in Google Scholar PubMed PubMed Central

121. Xu C, Ogburn ET, Guo Y, Desta Z. Effects of the CYP2B6*6 allele on catalytic properties and inhibition of CYP2B6 in vitro: implication for the mechanism of reduced efavirenz metabolism and other CYP2B6 substrates in vivo. Drug Metab Dispos 2012;40:717–25.10.1124/dmd.111.042416Search in Google Scholar PubMed PubMed Central

122. Kirchheiner J, Klein C, Meineke I, Sasse J, Zanger UM, Mürdter TE, et al. Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics 2003;13:619–26.10.1097/00008571-200310000-00005Search in Google Scholar PubMed

123. Johnstone E, Benowitz N, Cargill A, Jacob R, Hinks L, Day I, et al. Determinants of the rate of nicotine metabolism and effects on smoking behavior. Clin Pharmacol Ther 2006;80:319–30.10.1016/j.clpt.2006.06.011Search in Google Scholar PubMed

124. Rotger M, Tegude H, Colombo S, Cavassini M, Furrer H, Décosterd L, et al. Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals. Clin Pharmacol Ther 2007;81:557–66.10.1038/sj.clpt.6100072Search in Google Scholar PubMed

125. Watanabe T, Sakuyama K, Sasaki T, Ishii Y, Ishikawa M, Hirasawa N, et al. Functional characterization of 26 CYP2B6 allelic variants (CYP2B6.2-CYP2B6.28, except CYP2B6.22). Pharmacogenet Genomics 2010;20:459–62.10.1097/FPC.0b013e32833bba0eSearch in Google Scholar PubMed

126. Honda M, Muroi Y, Tamaki Y, Saigusa D, Suzuki N, Tomioka Y, et al. Functional characterization of CYP2B6 allelic variants in demethylation of antimalarial artemether. Drug Metab Dispos 2011;39:1860–5.10.1124/dmd.111.040352Search in Google Scholar PubMed

127. Xie HJ, Yasar U, Lundgren S, Griskevicius L, Terelius Y, Hassan M, et al. Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation. Pharmacogenomics J 2003;3:53–61.10.1038/sj.tpj.6500157Search in Google Scholar PubMed

128. Ariyoshi N, Ohara M, Kaneko M, Afuso S, Kumamoto T, Nakamura H, et al. Q172H replacement overcomes effects on the metabolism of cyclophosphamide and efavirenz caused by CYP2B6 variant with Arg262. Drug Metab Dispos 2011;39:2045–8.10.1124/dmd.111.039586Search in Google Scholar PubMed

129. Raccor BS, Claessens AJ, Dinh JC, Park JR, Hawkins DS, Thomas SS, et al. Potential contribution of cytochrome P450 2B6 to hepatic 4-hydroxycyclophosphamide formation in vitro and in vivo. Drug Metab Dispos 2012;40:54–63.10.1124/dmd.111.039347Search in Google Scholar PubMed PubMed Central

130. Bumpus NN, Kent UM, Hollenberg PF. Metabolism of efavirenz and 8-hydroxyefavirenz by P450 2B6 leads to inactivation by two distinct mechanisms. J Pharmacol Exp Ther 2006;318: 345–51.10.1124/jpet.106.102525Search in Google Scholar PubMed

131. Talakad JC, Kumar S, Halpert JR. Decreased susceptibility of the cytochrome P450 2B6 variant K262R to inhibition by several clinically important drugs. Drug Metab Dispos 2009;37:644–50.10.1124/dmd.108.023655Search in Google Scholar PubMed PubMed Central

132. Burger D, van der Heiden I, la Porte C, van der Ende M, Groeneveld P, Richter C, et al. Interpatient variability in the pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol 2006;61:148–54.10.1111/j.1365-2125.2005.02536.xSearch in Google Scholar PubMed PubMed Central

133. Mehlotra RK, Bockarie MJ, Zimmerman PA. CYP2B6 983T>C polymorphism is prevalent in West Africa but absent in Papua New Guinea: implications for HIV/AIDS treatment. Br J Clin Pharmacol 2007;64:391–5.10.1111/j.1365-2125.2007.02884.xSearch in Google Scholar PubMed PubMed Central

134. Li J, Menard V, Benish RL, Jurevic RJ, Guillemette C, Stoneking M, et al. Worldwide variation in human drug-metabolism enzyme genes CYP2B6 and UGT2B7: implications for HIV/AIDS treatment. Pharmacogenomics 2012;13:555–70.10.2217/pgs.11.160Search in Google Scholar PubMed PubMed Central

135. Zukunft J, Lang T, Richter T, Hirsch-Ernst KI, Nussler AK, Klein K, et al. A natural CYP2B6 TATA box polymorphism (-82T→C) leading to enhanced transcription and relocation of the transcriptional start site. Mol Pharmacol 2005;67:1772–82.10.1124/mol.104.008086Search in Google Scholar PubMed

136. Li H, Ferguson SS, Wang H. Synergistically enhanced CYP2B6 inducibility between a polymorphic mutation in CYP2B6 promoter and pregnane X receptor activation. Mol Pharmacol 2010;78:704–13.10.1124/mol.110.065185Search in Google Scholar PubMed PubMed Central

137. King J, Aberg JA. Clinical impact of patient population differences and genomic variation in efavirenz therapy. AIDS 2008;22:1709–17.10.1097/QAD.0b013e32830163adSearch in Google Scholar PubMed

138. Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004;18:2391–400.Search in Google Scholar

139. Tsuchiya K, Gatanaga H, Tachikawa N, Teruya K, Kikuchi Y, Yoshino M, et al. Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens. Biochem Biophys Res Commun 2004;319:1322–6.10.1016/j.bbrc.2004.05.116Search in Google Scholar PubMed

140. Rakhmanina NY, van den Anker JN. Efavirenz in the therapy of HIV infection. Expert Opin Drug Metab Toxicol 2010;6: 95–103.10.1517/17425250903483207Search in Google Scholar PubMed PubMed Central

141. Ribaudo HJ, Liu H, Schwab M, Schaeffeler E, Eichelbaum M, Motsinger-Reif AA, et al. Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS Clinical Trials Group study. J Infect Dis 2010;202:717–22.10.1086/655470Search in Google Scholar PubMed PubMed Central

142. Lubomirov R, di Iulio J, Fayet A, Colombo S, Martinez R, Marzolini C, et al., Swiss HIV Cohort Study. ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir. Pharmacogenet Genomics 2010;20:217–30.10.1097/FPC.0b013e328336eee4Search in Google Scholar PubMed

143. Maimbo M, Kiyotani K, Mushiroda T, Masimirembwa C, Nakamura Y. CYP2B6 genotype is a strong predictor of systemic exposure to efavirenz in HIV-infected Zimbabweans. Eur J Clin Pharmacol 2012;68:267–71.10.1007/s00228-011-1118-0Search in Google Scholar PubMed

144. Yimer G, Amogne W, Habtewold A, Makonnen E, Ueda N, Suda A, et al. High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study. Pharmacogenomics J 2011, in press.10.1038/tpj.2011.34Search in Google Scholar PubMed

145. Wyen C, Hendra H, Siccardi M, Platten M, Jaeger H, Harrer T, et al., German Competence Network for HIV/AIDS Coordinators. Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens. J Antimicrob Chemother 2011;66:2092–8.10.1093/jac/dkr272Search in Google Scholar PubMed

146. Lubomirov R, Colombo S, di Iulio J, Ledergerber B, Martinez R, Cavassini M, et al., Swiss HIV Cohort Study. Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study. J Infect Dis 2011;203:246–57.10.1093/infdis/jiq043Search in Google Scholar PubMed PubMed Central

147. Gatanaga H, Hayashida T, Tsuchiya K, Yoshino M, Kuwahara T, Tsukada H, et al. Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26. Clin Infect Dis 2007;45:1230–7.10.1086/522175Search in Google Scholar PubMed

148. Gatanaga H, Oka S. Successful genotype-tailored treatment with small-dose efavirenz. AIDS 2009;23:433–4.10.1097/QAD.0b013e32831940e3Search in Google Scholar PubMed

149. Nyakutira C, Röshammar D, Chigutsa E, Chonzi P, Ashton M, Nhachi C, et al. High prevalence of the CYP2B6 516G→T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe. Eur J Clin Pharmacol 2008;64:357–65.10.1007/s00228-007-0412-3Search in Google Scholar PubMed

150. Penzak SR, Kabuye G, Mugyenyi P, Mbamanya F, Natarajan V, Alfaro RM, et al. Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV-infected patients in Uganda. HIV Med 2007;8:86–91.10.1111/j.1468-1293.2007.00432.xSearch in Google Scholar PubMed

151. Mahungu T, Smith C, Turner F, Egan D, Youle M, Johnson M, et al. Cytochrome P450 2B6 516G→T is associated with plasma concentrations of nevirapine at both 200 mg twice daily and 400 mg once daily in an ethnically diverse population. HIV Med 2009;10:310–7.10.1111/j.1468-1293.2008.00689.xSearch in Google Scholar PubMed

152. Lehr T, Yuan J, Hall D, Zimdahl-Gelling H, Schaefer HG, Staab A, et al. Integration of absorption, distribution, metabolism, and elimination genotyping data into a population pharmacokinetic analysis of nevirapine. Pharmacogenet Genomics 2011;21: 721–30.10.1097/FPC.0b013e32834a522eSearch in Google Scholar PubMed

153. Yuan J, Guo S, Hall D, Cammett AM, Jayadev S, Distel M, et al., Nevirapine Toxicogenomics Study Team. Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent. AIDS 2011;25:1271–80.10.1097/QAD.0b013e32834779dfSearch in Google Scholar PubMed PubMed Central

154. Crettol S, Déglon JJ, Besson J, Croquette-Krokkar M, Gothuey I, Hämmig R, et al. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther 2005;78:593–604.10.1016/j.clpt.2005.08.011Search in Google Scholar PubMed

155. Eap CB, Crettol S, Rougier JS, Schläpfer J, Sintra Grilo L, Déglon JJ, et al. Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther 2007;81:719–28.10.1038/sj.clpt.6100120Search in Google Scholar PubMed

156. Bunten H, Liang WJ, Pounder D, Seneviratne C, Osselton MD. CYP2B6 and OPRM1 gene variations predict methadone-related deaths. Addict Biol 2011;16:142–4.10.1111/j.1369-1600.2010.00274.xSearch in Google Scholar PubMed

157. Levran O, Peles E, Hamon S, Randesi M, Adelson M, Kreek MJ. CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction. Addict Biol 2011, in press.10.1111/j.1369-1600.2011.00349.xSearch in Google Scholar PubMed PubMed Central

158. Chang TK, Weber GF, Crespi CL, Waxman DJ. Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Res 1993;53:5629–37.Search in Google Scholar

159. Xie H, Griskevicius L, Ståhle L, Hassan Z, Yasar U, Rane A, et al. Pharmacogenetics of cyclophosphamide in patients with hematological malignancies. Eur J Pharm Sci 2006;27:54–61.10.1016/j.ejps.2005.08.008Search in Google Scholar PubMed

160. Nakajima M, Komagata S, Fujiki Y, Kanada Y, Ebi H, Itoh K, et al. Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patients. Pharmacogenet Genomics 2007;17:431–45.10.1097/FPC.0b013e328045c4fbSearch in Google Scholar PubMed

161. Helsby N, Tingle M. The importance of correct assignment of CYP2B6 genetic variants with respect to cyclophosphamide metabolizer status. Am J Hematol 2011;86:383–4.10.1002/ajh.21987Search in Google Scholar PubMed

162. Helsby NA, Tingle MD. Which CYP2B6 variants have functional consequences for cyclophosphamide bioactivation? Drug Metab Dispos 2012;40:635–7.10.1124/dmd.111.043646Search in Google Scholar PubMed