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Pharmacogenomics in and its Influence on Pharmacokinetics

  • Guy MontayEmail author
  • Jochen Maas
  • Roland Wesch
Living reference work entry

Abstract

CYP1A2 is involved to a major extent in the metabolism of several drugs (imipramine, clozapine, fluvoxamine, olanzapine, theophylline, acetaminophen, propranolol, and tacrine) as well as of diet components (methylxanthines), endogenous substrates (estrogens), numerous aryl, aromatic and heterocyclic amines, and polycyclic aromatic hydrocarbons. It is inducible, notably by cigarette smoking, diet habits such as consumption of cruciferous vegetables (e.g., broccoli, watercress, collard greens, Brussels sprouts, and mustard) and of charbroiled meats, some drugs (omeprazole, phenytoin, and rifampicin) and is a target enzyme for the development of some cancers. Up to now, more than 25 CYP1A2 alleles have been detected. Probe drugs for CYP1A2 phenotyping are caffeine and theophylline. For safety concerns and drug availability, the preferred probe is caffeine. Caffeine 3-demethylation is mediated by CYP1A2, and accounts for 80% of caffeine clearance. Caffeine is also a probe drug for N-acetyltransferase and xanthine oxidase (Clin Pharmacol Ther 53:203–514, 1993).

II.T.1

Phase I enzymes

 II.T.1.1

CYP1A2

 II.T.1.2

CYP2C9

 II.T.1.3

CYP2C19

 II.T.1.4

CYP2D6

 II.T.1.5

CYP3A

 II.T.1.6

Other CYPS

 II.T.1.6.1

CYP2A6

 II.T.1.6.2

CYP2B6

 II.T.1.6.3

CYP2C8

 II.T.1.6.4

CYP2E1

II.T.2

Phase II enzymes

 II.T.2.1

N-acetyltransferases

 II.T.2.2

Uridine diphosphate glucuronosyltransferases

 II.T.2.3

Methyltransferases

 II.T.2.4

Glutathione S-transferases and sulfotransferases

The understanding of the role of pharmacogenetics in drug metabolism expanded greatly in the 1990s. This is mainly due to technological improvements in gene scanning and gene variant identification. The number of variant alleles identified for genes coding for drug metabolizing enzymes (DME) considerably increased in the early 2000s, and continues to increase. The clinical consequences – or at least genotyping–phenotyping relationships – of DME polymorphisms have not been demonstrated for all variants. In the text below, only those DME allele variants will be mentioned for which significant changes in enzyme activity have been found using probe drugs. Comprehensive information on the nomenclature of cytochrome P450 (CYP) alleles can be found at www.imm.ki.se/CYPalleles and Phase I and Phase II DMEs at www.pharmgkb.org/index.jsp.

References and Further Reading

  1. Abernathy DR, Todd EL (1985) Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives. Eur J Clin Pharmacol 28:425–428CrossRefGoogle Scholar
  2. Alfirevic A, Stalford AC, Vilar FJ et al (2003) Slow acetylator phenotype and genotype in HIV-positive patients with sulphamethoxazole hypersensitivity. Br J Clin Pharmacol 55:158–165PubMedPubMedCentralCrossRefGoogle Scholar
  3. Andersson T, Regardh CG, Dahl-Puustinen ML, Bertilsson L (1990) Slow omeprazole metabolizers are also poor S-mephenytoin hydroxylators. Ther Drug Monit 12:415–416PubMedCrossRefGoogle Scholar
  4. Ando Y, Saka H, Asai G et al (1998) OGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan. Ann Oncol 9:845–847PubMedCrossRefGoogle Scholar
  5. Bahadur N, Leathart JBS, Mutch E et al (2002) CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6α-hydroxylase activity in human liver microsomes. Biochem Pharmacol 64:1579–1589PubMedCrossRefGoogle Scholar
  6. Balian JD, Sukhova N, Harris JW et al (1995) The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study. Clin Pharmacol Ther 57:662–669PubMedCrossRefGoogle Scholar
  7. Bapiro TE, Hasler JA, Ridderström M, Masimirembwa CM (2002) The molecular and enzyme kinetic basis for the diminished activity of the cytochrome P450 2D6*17 variant. Biochem Pharmacol 64:1387–1398PubMedCrossRefGoogle Scholar
  8. Baud-Camus F, Marquet P, Soursac M et al (2001) Determination of N-acetylation phenotype using caffeine as a metabolic probe and high-performance liquid chromatography with either ultraviolet detection or electrospray mass spectrometry. J Chromatogr B 760:55–63CrossRefGoogle Scholar
  9. Bertilsson L, Lou YQ, Du YL et al (1992) Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 51:388–397PubMedCrossRefGoogle Scholar
  10. Bertilsson L, Dahl ML, Dalen P, Al-Shurbaji A (2002) Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 53:111–122PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bolden RD, Hoke SHII, Eichhold TH et al (2002) Semi-automated liquid–liquid back extraction in a 96-well format to decrease sample preparation time for the determination of dextromethorphan and dextrorphan in human plasma. J Chromatogr B 772:1–10CrossRefGoogle Scholar
  12. Brentano C, Jaillon P (2001) Variability of cytochrome P450 1A2 activity over time in young and elderly healthy volunteers. Br J Clin Pharmacol 52:601–604CrossRefGoogle Scholar
  13. Butcher NJ, Boukouvala S, Sim E, Minchin RF (2002) Pharmacogenetics of the arylamine N-acetyltransferases. Pharmacogenomics J 2:30–42PubMedCrossRefGoogle Scholar
  14. Campbell ME, Spielberg SP, Kalow W (1987) A urinary metabolic ratio that reflects systemic caffeine clearance. Clin Pharmacol Ther 42:157–165PubMedCrossRefGoogle Scholar
  15. Caubet MS, Comte B, Brazier JL (2004) Determination of urinary 13C-caffeine metabolites by liquid chromatography–mass spectrometry: the use of metabolic ratios to assess CYP1A2 activity. J Pharm Sci Biomed Anal 34:379–389CrossRefGoogle Scholar
  16. Chang M, Dahl ML, Tybring G et al (1995) Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 5:358–363PubMedCrossRefGoogle Scholar
  17. Chladek J, Zimova G, Martinkova J, Tuma I (1999) Intra-individual variability and influence of urine collection period on dextromethorphan metabolic ratios in healthy subjects. Fundam Clin Pharmacol 13:508–515PubMedCrossRefGoogle Scholar
  18. Chladek J, Zimova G, Beranek M, Martinkova J (2000) In-vivo indices of CYP2D6 activity: comparison of dextromethorphan metabolic ratios in 4-h urine and 3-h plasma. Eur J Clin Pharmacol 56:651–657PubMedCrossRefGoogle Scholar
  19. Chou WH, Yan FX, Robbins-Weilert DK et al (2003) Comparison of two CYP2D6 genotyping methods and assessment of genotype–phenotype relationships. Clin Chem 49:542–551PubMedCrossRefGoogle Scholar
  20. Cok I, Kocabas NA, Cholerton S et al (2001) Determination of coumarin metabolism in Turkish population. Human Exp Pharmacol 20:179–184Google Scholar
  21. Commandeur JNM, Stintjes GJ, Vermeulen NPE (1995) Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Pharmacol Rev 47:271–330PubMedGoogle Scholar
  22. Csillag K, Vereczkey L, Gachalyi B (1989) Simple high-performance liquid chromatographic method for the determination of tolbutamide and its metabolites in human plasma and urine using photo-diode array detection. J Chromatogr 490:355–363PubMedGoogle Scholar
  23. Dai D, Zeldin DC, Blaisdell JA et al (2001) Polymorphisms in CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 11:597–607PubMedCrossRefGoogle Scholar
  24. Daly AK, King BP (2003) Pharmacogenetics of anticoagulants. Pharmacogenetics 13:247–252PubMedCrossRefGoogle Scholar
  25. Eap CB, Buclin T, Hustert E et al (2004a) Pharmacokinetics of midazolam in CYP3A4- and CYP3A5-genotyped subjects. Eur J Clin Pharmacol 60:231–236PubMedGoogle Scholar
  26. Eap CB, Buclin T, Cucchia G et al (2004b) Oral administration of midazolam (75 μg) as an in vivo probe for CYP3A activity. Eur J Clin Pharmacol 60:237–246PubMedGoogle Scholar
  27. Endo T, Nakajima M, Fukami T et al (2008) Genetic polymorphisms of CYP2A6 affect the in-vivo pharmacokinetics of pilocarpine. Pharmacogenet Genomics 18:761–772PubMedCrossRefGoogle Scholar
  28. Ernstgard L, Warholm M, Johanson G (2004) Robustness of chlorzoxazone as an in vivo measure of cytochrome P450 2E1 activity. Br J Clin Pharmacol 58:190–200PubMedPubMedCentralCrossRefGoogle Scholar
  29. Evans WE (2004) Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit 26:186–191PubMedCrossRefGoogle Scholar
  30. Faucette SR, Hawke L, Lecluyse RL et al (2000) Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 28:1222–1230PubMedPubMedCentralGoogle Scholar
  31. Fischer MB, Paine MF, Strelevitz TJ, Wrighton SA (2001) The role of hepatic and extrahepatic UDP–glucuronyltransferases in human drug metabolism. Drug Metab Rev 33:273–297CrossRefGoogle Scholar
  32. Frison G, Tedeschi L, Maietti S, Ferrara SD (2001) Determination of midazolam in plasma by solid-phase microextraction and gas chromatography/mass spectrometry. Rapid Commun Mass Spectrom 15:2497–2501PubMedCrossRefPubMedCentralGoogle Scholar
  33. Frye RF, Stiff DD (1996) Determination of chlorzoxazone and 6-hydroxy chlorzoxazone in human plasma and urine by high performance liquid chromatography. J Chromatogr B 686:291–296CrossRefGoogle Scholar
  34. Frye RF, Adedoyin A, Mauro K et al (1998) Use of chlorzoxazone as an in vivo probe of cytochrome P450 2E1: choice of dose and phenotypic trait measure. J Clin Pharmacol 38:82–89PubMedPubMedCentralGoogle Scholar
  35. Fuchs P, Haefeli WE, Ledermann HR, Wenk M (1999) Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-acetyltransferase2 and CYP1A2 activities. Eur J Clin Pharmacol 54:869–876PubMedCrossRefPubMedCentralGoogle Scholar
  36. Fuhr U, Rost LK (1994) Simple and reliable CYP1A2 phenotyping by the paraxanthine/caffeine ratio in plasma and saliva. Pharmacogenetics 4:109–116PubMedCrossRefPubMedCentralGoogle Scholar
  37. Fujieda M, Yamazaki H, Saito T et al (2004) Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behaviour and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis 25:2451–2458PubMedCrossRefPubMedCentralGoogle Scholar
  38. Gaedigk A, Bradford LD, Marcucci KA, Leeder JS (2002) Unique CYP2D6 activity distribution and genotype–phenotype discordance in black Americans. Clin Pharmacol Ther 72:76–89PubMedCrossRefPubMedCentralGoogle Scholar
  39. Gafni I, Nolte H, Tyndale R et al (2001) Resolving the roles of CYP2C19 and CYP3A4 in the metabolism of omeprazole in vivo using chronic omeprazole and ketoconazole. FASEB J 15:A918Google Scholar
  40. Garcia-Martin E, Martinez C, Tabarés B et al (2004) Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther 76:119–127PubMedCrossRefGoogle Scholar
  41. Glatt H, Meinl W (2004) Pharmacogenetics of soluble sulfotransferases (SULTs). Naunyn Schmiedeberg's Arch Pharmacol 369:55–68CrossRefGoogle Scholar
  42. Gonzalez HM, Romero EM, Peregrina AA et al (2003) CYP2C19- and CYP3A4-dependent omeprazole metabolism in west Mexicans. J Clin Pharmacol 43:1211–1215PubMedPubMedCentralGoogle Scholar
  43. Gorski JC, Jones DR, Haehner-Daniels BD et al (1998) The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin Pharmacol Ther 64:133–143PubMedCrossRefPubMedCentralGoogle Scholar
  44. Grant DM, Tang BK, Kalow W (1984) A simple test for acetylator phenotype using caffeine test. Br J Clin Pharmacol 17:459–464PubMedPubMedCentralCrossRefGoogle Scholar
  45. Guillemette C (2003) Pharmacogenomics of human UDP–glucuronosyltransferase enzymes. Pharmacogenomics J 3:136–158PubMedCrossRefPubMedCentralGoogle Scholar
  46. Hadasova E, Franke G, Zschiesche M et al (1996) Debrisoquin 4-hydroxylation and sulphamethazine N-acetylation in patients with schizophrenia and major depression. Br J Clin Pharmacol 41:428–431PubMedPubMedCentralCrossRefGoogle Scholar
  47. Hägg S, Spigset O, Dahlqvist R (2001) Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol 51:169–173PubMedPubMedCentralCrossRefGoogle Scholar
  48. Han XM, Ou-Yang DS, Lu PX et al (2001) Plasma caffeine metabolite ratio (17X/137X) in vivo associated with G-2964A and C734A polymorphisms of human CYP1A2. Pharmacogenetics 11:429–435PubMedCrossRefPubMedCentralGoogle Scholar
  49. Hansen LL, Brosen K (1999) Quantitative determination of tolbutamide and its metabolites in human plasma and urine by high-performance liquid chromatography and UV detection. Ther Drug Monitor 21:664–671CrossRefGoogle Scholar
  50. Härtter S, Baier D, Dingemanse J et al (1996) Automated determination of dextromethorphan and its main metabolites in human plasma by high-performance liquid chromatography and column switching. Ther Drug Monit 18:297–303PubMedCrossRefGoogle Scholar
  51. Hayes JD, Strange RC (2000) Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology 61:154–166PubMedCrossRefGoogle Scholar
  52. Hesse LM, He P, Krishnaswamy S et al (2004) Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Pharmacogenetics 14:225–238PubMedCrossRefGoogle Scholar
  53. Hoskins JM, Shenfield GM, Gross AS (1997) Modified high-performance liquid chromatographic method to measure both dextromethorphan and proguanil for oxidative phenotyping. J Chromatogr B 696:81–87CrossRefGoogle Scholar
  54. Hu OY, Tang HS, Chang WH, Hu TM (1998) Novel single-point plasma or saliva dextromethorphan method for determining CYP2D6 activity. J Pharmacol Exp Ther 285:955–960PubMedGoogle Scholar
  55. Innocenti F, Iyer L, Ratain MJ (2000) Pharmacogenetics: a tool for individualizing antineoplastic therapy. Clin Pharmacokinet 39:315–325PubMedCrossRefGoogle Scholar
  56. Innocenti F, Undvia SD, Iyer L et al (2004) Genetic variants in the UDP–glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 8:1382–1388CrossRefGoogle Scholar
  57. Ishizaki T, Sohn DR, Kobayashi K et al (1994) Interethnic differences in omeprazole metabolism in the two S-mephenytoin hydroxylation phenotypes studied in Caucasians and Orientals. Ther Drug Monit 16:214–215PubMedCrossRefGoogle Scholar
  58. Iyer L, Das S, Janish L et al (2002) UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2:43–47PubMedCrossRefGoogle Scholar
  59. Jetter A, Kinzig-Schippers M, Skott A et al (2004) Cytochrome P450 2C9 phenotyping using low-dose tolbutamide. Eur J Clin Pharmacol 60:165–175PubMedCrossRefGoogle Scholar
  60. Johansson I, Oscarson M, Yue QY et al (1994) Genetic analysis of the Chinese cytochrome P450D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquin hydroxylation. Mol Pharmacol 46:452–459PubMedGoogle Scholar
  61. Kalow W, Tang BK (1991) Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther 50:508–519PubMedCrossRefGoogle Scholar
  62. Kalow W, Tang BK (1993) The use of caffeine for enzyme assays: a critical appraisal. Clin Pharmacol Ther 53:203–514CrossRefGoogle Scholar
  63. Kanazawa H, Atsumi R, Matsushima Y et al (2000) Determination of theophylline and its metabolites in biological samples by liquid chromatography–mass spectrometry. J Chromatogr A 870:87–96PubMedCrossRefGoogle Scholar
  64. Kanazawa H, Okada A, Matsushima Y et al (2002) Determination of omeprazole and its metabolites in human plasma by liquid chromatography–mass spectrometry. J Chromatogr A 949:1–9PubMedCrossRefGoogle Scholar
  65. Kashuba ADM, Bertino JS, Kearns GL et al (1998) 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 63:540–551PubMedCrossRefGoogle Scholar
  66. Kidd RS, Curry TB, Gallagher S et al (2001) Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics 11:803–808PubMedCrossRefGoogle Scholar
  67. Kim RB, O’Shea D, Wilkinson GR (1995) Interindividual variability of chlorzoxazone 6-hydroxylation in men and women and its relationship to CYP2E1 genetic polymorphisms. Clin Pharmacol Ther 57:645–655PubMedCrossRefGoogle Scholar
  68. Kimura M, Ieri I, Wada Y, Mamyia K (1999) Reliability of the omeprazole hydroxylation index and length of therapy. Br J Clin Pharmacol 47:115–119PubMedPubMedCentralCrossRefGoogle Scholar
  69. Kirchheiner J, Bauer S, Meineke I et al (2002a) Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers. Pharmacogenetics 12:101–109PubMedCrossRefGoogle Scholar
  70. Kirchheiner J, Brockmöller J, Meineke I et al (2002b) Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin Pharmacol Ther 71:286–296PubMedCrossRefGoogle Scholar
  71. Kirchheiner J, Störmer E, Meisel C et al (2003a) Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics 13:473–480PubMedCrossRefGoogle Scholar
  72. Kirchheiner J, Klein C, Meineke I et al (2003b) Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics 13:619–626PubMedCrossRefGoogle Scholar
  73. Kita T, Tanigawara Y, Chikizawa S et al (2001) N-acetyltransferase2 genotype correlated with isoniazid acetylation in Japanese tuberculous patients. Biol Pharm Bull 24:544–549PubMedCrossRefGoogle Scholar
  74. Klebovitch I, Rautio A, Salonpää P et al (1995) Antipyrine, coumarin and glipizide affect N-acetylation measured by caffeine test. Biomed Pharmacother 49:225–227CrossRefGoogle Scholar
  75. Krul C, Hageman G (1998a) Analysis of urinary caffeine metabolites to assess biotransformation enzyme activities by reverse-phase high-performance liquid chromatography. J Chromatogr B 709:24–27Google Scholar
  76. Krul C, Hageman G (1998b) Analysis of urinary caffeine metabolites to assess biotransformation enzyme activities by reverse-phase high-performance liquid chromatography. J Chromatogr B 709:27–34CrossRefGoogle Scholar
  77. Lagerstrom PO, Persson BA (1984) Determination of omeprazole and its metabolites in plasma and urine by liquid chromatography. J Chromatogr A 309:347–356CrossRefGoogle Scholar
  78. Laine K, Tybring G, Bertilsson L (2000) No sex-related difference 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 68:151–159PubMedCrossRefGoogle Scholar
  79. Lamba JK, Lin YS, Schuety EG, Thummel KE (2002) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 54:1271–1294PubMedPubMedCentralCrossRefGoogle Scholar
  80. Lang T, Klein K, Richter T et al (2004) Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles. JPET 311:34–43CrossRefGoogle Scholar
  81. Lecomte T, Landi B, Beaune P et al (2006) Glutathione S-transferase P1 polymorphism (Ile 105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin Cancer Res 12:3050–3056PubMedCrossRefGoogle Scholar
  82. Lee CR, Pieper JA, Hinderliter AL et al (2002a) Evaluation of cytochrome P450 2C9 metabolic activity with tolbutamide in CYP2C9*1 heterozygotes. Clin Pharmacol Ther 72:562–571PubMedCrossRefGoogle Scholar
  83. Lee CR, Goldstein JA, Pieper JA (2002b) Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in vitro and human data. Pharmacogenetics 12:251–263PubMedCrossRefGoogle Scholar
  84. Lee JI, Chaves-Gnecco D, Amico JA et al (2002c) Application of simultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping. Clin Pharmacol Ther 72:718–728PubMedCrossRefGoogle Scholar
  85. Lee CR, Pieper JA, Reginald FF et al (2003) Tolbutamide, flurbiprofen and losartan as probes of CYP2C9 activity in humans. J Clin Pharmacol 43:84–91PubMedGoogle Scholar
  86. Lepper ER, Hicks JK, Verweij J et al (2004) Determination of midazolam in human plasma by liquid chromatography with mass-spectrometric detection. J Chromatogr B 806:305–310CrossRefGoogle Scholar
  87. Lieber CS (1997) Cytochrome P-450 2E1: its physiological and pathological role. Physiol Rev 77:517–544PubMedPubMedCentralCrossRefGoogle Scholar
  88. Lin YS, Lockwood GF, Graham MA et al (2001) In-vivo phenotyping for CYP3A by single-point determination of midazolam plasma concentration. Pharmacogenetics 11:781–791PubMedCrossRefGoogle Scholar
  89. Lown K, Kolars J, Turgeon K et al (1992) The erythromycin breath test selectively measures P450IIIA in patients with severe liver disease. Clin Pharmacol Ther 52:229–238CrossRefGoogle Scholar
  90. Lucas D, Ferrara R, Gonzalez E et al (1999) Chlorzoxazone: a selective probe for phenotyping CYP2E1 in humans. Pharmacogenetics 9:377–388PubMedCrossRefGoogle Scholar
  91. McCrea J, Prueksaritanont T, Gertz BJ et al (1999) Concurrent administration of the erythromycin breath test (EBT) and oral midazolam as in vivo probes for CYP3A activity. J Clin Pharmacol 39:1212–1220PubMedGoogle Scholar
  92. McCune J, Lindley C, Decker JL et al (2001) Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan. J Clin Pharmacol 41:723–731PubMedCrossRefGoogle Scholar
  93. McLeod HL, Evans WE (2001) Pharmacogenomics: unlocking the human genome for better drug therapy. Annu Rev Pharmacol Toxicol 41:101–121PubMedCrossRefGoogle Scholar
  94. Meisel P (2002) Arylamine N-acetyltransferases and drug response. Pharmacogenomics 3:349–366PubMedCrossRefGoogle Scholar
  95. Meisel P, Schroeder C, Wulff K, Siegmund W (1997) Relationship between human genotype and phenotype of N-acetyltransferase (NAT2) as estimated by discriminant analysis and multiple linear regression: 1. Genotype and N-acetylation in vivo. Pharmacogenetics 7:241–246PubMedCrossRefGoogle Scholar
  96. Meyer UA (2000) Pharmacogenetics and adverse drug reactions. Lancet 356:1667–1671CrossRefGoogle Scholar
  97. Meyer UA, Zanger UM (1997) Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol 37:269–296PubMedCrossRefGoogle Scholar
  98. Miners JO, Birkett DJ (1998) Cytochrome P450 2C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 45:525–538PubMedPubMedCentralCrossRefGoogle Scholar
  99. Mongey AB, Sim E, Risch A, Hess E (1999) Acetylation status is associated with serological change but not clinically significant disease in patients receiving procainamide. J Rheumatol 26:1721–1726PubMedGoogle Scholar
  100. Morin S, Bodin L, Loriot MA et al (2004) Pharmacogenetics of acenocoumarol. Clin Pharmacol Ther 75:403–414PubMedCrossRefGoogle Scholar
  101. Niemi M, Leathart JB, Neuvonen M et al (2003) Polymorphisms in CYP2C8 is associated with reduced plasma concentrations of repaglinide. Clin Pharmacol Ther 74:380–387PubMedCrossRefGoogle Scholar
  102. Nordmark A, Lundgren S, Cnattingius S et al (1999) Dietary caffeine as a probe agent for assessment of cytochrome P450 1A2 activity in random urine samples. Br J Clin Pharmacol 47:397–402PubMedPubMedCentralGoogle Scholar
  103. Nordmark A, Lundgren S, Ask B et al (2002) The effect of the CYP1A2*F mutation on CYP1A2 inducibility in pregnant women. Br J Clin Pharmacol 54:504–510PubMedPubMedCentralCrossRefGoogle Scholar
  104. Nyeki A, Buclin T, Biollaz J, Decosterd LA (2002) NAT2 and CYP1A2 phenotyping with caffeine: head-to-head comparison of AFMU vs AAMU in the urine metabolite ratios. Br J Clin Pharmacol 55:62–67CrossRefGoogle Scholar
  105. O’Neil WM, Drobitch RK, MacArthur RD et al (2000) Acetylator phenotype and genotype in patients infected with HIV: discordance between methods for phenotype determination and genotype. Pharmacogenetics 10:171–182PubMedCrossRefGoogle Scholar
  106. Okumura K, Kita T, Chikazawa S et al (1997) Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism. Clin Pharm Ther 61:509–517CrossRefGoogle Scholar
  107. Ono S, Hatanaka T, Hotta H et al (1995) Chlorzoxazone is metabolized by human CYP1A2 as well as by human CYP2E1. Pharmacogenetics 5:143–150PubMedCrossRefGoogle Scholar
  108. Oscarson M (2001) Genetic polymorphisms in the cytochrome P450 2A6 (CYP2A6) gene: implications for interindividual differences in nicotine metabolism. Drug Metab Dispos 29:91–95PubMedGoogle Scholar
  109. Ou-Yang DS, Huang SL, Wang W et al (2000) Phenotypic polymorphism and gender-related differences of CYP1A2 activity in a Chinese population. Br J Clin Pharmacol 49:145–151PubMedPubMedCentralCrossRefGoogle Scholar
  110. Paoluzzi L, Singh AS, Price DK, Danesi R (2004) Influence of genetic variants in UGT1A1 and UGT1A9 in the in vivo glucuronidation of SN-38. J Clin Pharmacol 44:854–860PubMedGoogle Scholar
  111. Pelkonen O, Rautio A, Raunio H, Pasanene M (2000) CYP2A6: a human coumarin 7-hydroxylase. Toxicology 144:139–147PubMedCrossRefGoogle Scholar
  112. Queiroz RH, Dreossi SA, Carvalho D (1997) A rapid, specific, and sensitive method for the determination of acetylation phenotype using dapsone. J Anal Toxicol 21:203–207PubMedCrossRefGoogle Scholar
  113. Rane A (1999) Phenotyping of drug metabolism in infants and children: potentials and problems. Pediatrics 104:640–643PubMedGoogle Scholar
  114. Rasmussen BB, Bosen K (1996) Determination of urinary metabolites of caffeine for the assessment of cytochrome P450 1A2, xanthine oxidase and N-acetyltransferase activity in humans. Ther Drug Monitor 18:254–262CrossRefGoogle Scholar
  115. Raunio H, Rautio A, Gullstén H, Pelkonen O (2001) Polymorphisms of CYP2A6 and its practical consequences. Br J Clin Pharmacol 52:357–363PubMedPubMedCentralCrossRefGoogle Scholar
  116. Relling MV, Lin JS, Ayers GD, Evans EE (1992) Racial and gender differences in N-acetyltransferase, xanthine oxidase and CYP1A2* activities. Clin Pharmacol Ther 52:643–658PubMedCrossRefGoogle Scholar
  117. Rivory LP, Slaviero KA, Seale JP et al (2000) Optimizing the erythromycin breath test for use in cancer patients. Clin Cancer Res 6:3480–3485PubMedGoogle Scholar
  118. Rogers JF, Nafziger AN, Bertino JS (2002) Pharmacogenetics affects dosing, efficacy, and toxicity of cytochrome P450-metabolized drugs. Am J Med 113:746–750PubMedGoogle Scholar
  119. Rosemary J, Adithan C (2007) The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance. Curr Clin Pharmacol 2:93–109PubMedCrossRefGoogle Scholar
  120. Rostami-Hodjegan A, Nurminen S, Jackson PR, Tucker GT (1996) Caffeine urinary metabolic ratios as markers of enzyme activity: a theoretical assessment. Pharmacogenetics 6:121–149PubMedCrossRefGoogle Scholar
  121. Rothen JP, Haefeli WE, Meyer UA et al (1998) Acetominophen is an inhibitor of hepatic N-acetyltransferase 2 in vitro and in vivo. Pharmacogenetics 8:553–559PubMedCrossRefGoogle Scholar
  122. Sachse C, Brockmöller J, Bauer S, Roots I (1997) Cytochromes P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 60:284–295PubMedPubMedCentralGoogle Scholar
  123. Sachse S, Bhambra U, Smith G et al (2003) Polymorphisms in the cytochrome P4501A2 gene (CYP1A2) in colorectal cancer patients and control: allele frequencies, linkage disequilibrium and influence on caffeine metabolism. Br J Clin Pharmacol 55:68–76PubMedPubMedCentralCrossRefGoogle Scholar
  124. Saitoh A, Fletcher C, Brundage R et al (2007) Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6–G516T polymorphism. J Acquir Immune Defic Syndr 45:280–285PubMedGoogle Scholar
  125. Sandberg M, Johansson I, Christensen M et al (2004) The impact of CYP2C9 genetics and oral contraceptives on cytochrome P450 2C9 phenotype. Drug Metab Dispos 32:484–489PubMedCrossRefGoogle Scholar
  126. Schmid B, Bircher J, Preisig R, Küpfer A (1985) Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther 38:618–624PubMedCrossRefGoogle Scholar
  127. Schreiber-Deturmeny E, Bruguerolle B (1996) Simultaneous high-performance liquid chromatographic determination of caffeine and theophylline for routine drug monitoring in human plasma. J Chromatogr B 677:305–312CrossRefGoogle Scholar
  128. Schwarz UI (2003) Clinical relevance of genetic polymorphisms in the human CYP2C9 gene. Eur J Clin Invest 33:23–30PubMedCrossRefGoogle Scholar
  129. Scoot 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 13:2305–2319CrossRefGoogle Scholar
  130. Scordo MG, Aklillu E, Dahl ML et al (2001) Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol 52:447–450PubMedPubMedCentralCrossRefGoogle Scholar
  131. Scordo MG, Caputi AP, D’Arrigo C et al (2004) Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Pharmacol Res 50:195–200PubMedCrossRefGoogle Scholar
  132. Sekino K, Kubota T, Okada Y et al (2003) Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics in healthy Japanese subjects. Eur J Clin Pharmacol 59:589–592PubMedCrossRefGoogle Scholar
  133. Sevilla-Mantilla C, Ortega L, Agundez JA et al (2004) Leflunomide acute hepatitis. Dig Liver Dis 36:82–84PubMedCrossRefGoogle Scholar
  134. Shimada Y, Yamazki H, Mimura M et al (1994) Inter-individual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:413–423Google Scholar
  135. Shirley KL, Hon YY, Penzak S et al (2003) Correlation of cytochrome P450 1A2 activity using caffeine phenotyping and olanzapine disposition in healthy volunteers. Neuropsychopharmacology 25:961–966CrossRefGoogle Scholar
  136. Shong JH, Yoon YR, Kim KA et al (2002) Effects of CYP2C9 and CYP2C19 genetic polymorphisms on the disposition and blood glucose lowering response to tolbutamide in humans. Pharmacogenetics 12:111–119CrossRefGoogle Scholar
  137. Shou M, Korzekwa KR, Brooks EN et al (1997) Role of human hepatic cytochrome P450 1A2 and 3A4 in the metabolic activation of estrone. Carcinogenesis 18:207–214PubMedCrossRefGoogle Scholar
  138. Simon T, Becquemont L, Hamon B et al (2003) Determination of –3858G-A and 164C-A genetic polymorphisms of CYP1A2 in blood and saliva by rapid alleleic discrimination: large difference in the prevalence of the –3858G-A mutation between Caucasians and Asians. Eur J Clin Pharmacol 59:343–346CrossRefGoogle Scholar
  139. Tamminga WJ, Werner J, Oosterhuis B et al (1999) CYP2D6 and CYP2C19 activity in a large population of Dutch healthy volunteers: indications for oral contraceptive-related gender differences. Eur J Clin Pharmacol 55:177–184PubMedCrossRefGoogle Scholar
  140. Tang BK, Kadar D, Qian L et al (1991) Caffeine as a metabolic probe: validation of its use for acetylator phenotyping. Clin Pharmacol Ther 49:648–657PubMedCrossRefGoogle Scholar
  141. Tetlow N, Robinson A, Mantle T, Board P (2004) Polymorphism of human mu class glutathione transferases. Pharmacogenetics 14:359–368PubMedCrossRefGoogle Scholar
  142. Thummel KE, Shen DD, Podoll TD et al (1994) Use of midazolam as a human cyotochrome P450 3A probe: in vitro–in vivo correlations in liver transplant patients. J Pharmacol Exp Ther 271:549–556PubMedGoogle Scholar
  143. Thummel KE, O’Shea D, Paine MF et al (1996) Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 59:491–502PubMedCrossRefGoogle Scholar
  144. Tukey RH, Strassburg CP (2000) Human UDP–glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40:581–616PubMedCrossRefGoogle Scholar
  145. Turpeinen M, Raunio H, Pelkonen O (2006) The functional role of CYP2B6 in human drug metabolism: substrates and inhibitors in vitro, in vivo and in silico. Curr Drug Metabol 7:705–714CrossRefGoogle Scholar
  146. Tybring G, Bottiger Y, Wyden J, Bertilsson L (1997) Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19. Clin Pharmacol Ther 62:129–137PubMedCrossRefGoogle Scholar
  147. Veronese ME, Miners JO, Randles D et al (1990) Validation of the tolbutamide metabolic ratio for population screening with use of sulfaphenazole to produce model phenotypic poor metabolizers. Clin Pharmacol Ther 47:403–411PubMedCrossRefGoogle Scholar
  148. Veronese ME, Miners JO, Ress DLP, Birkett DJ (1993) Tolbutamide hydroxylation in humans: lack of bimodality in 106 healthy subjects. Pharmacogenetics 3:86–93PubMedCrossRefGoogle Scholar
  149. Versuyft C, Robert A, Morin S et al (2003) Genetic and environmental risk factors for oral anticoagulant overdose. Eur J Clin Pharmacol 58:739–745CrossRefGoogle Scholar
  150. Villeneuve L, Girard H, Fortier LC et al (2003) Novel functional polymorphisms in the UGT1A7 and UGT1A9 glucuronidating enzymes in Caucasian and African-American subjects and their impact on the metabolism of 7-ethyl-10-hydroxycamptothecin and flavopiridol anticancer drugs. J Pharmacol Exp Ther 307:117–128PubMedCrossRefGoogle Scholar
  151. von Richter O, Burk O, Fromm MF et al (2004) Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther 75:172–183CrossRefGoogle Scholar
  152. Ward B, Gorski C, Jones D et al (2003) 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. JPET 306:287–300CrossRefGoogle Scholar
  153. Watkins PB (1994) Noninvasive tests of CYP3A enzymes. Pharmacogenetics 4:171–184PubMedCrossRefPubMedCentralGoogle Scholar
  154. Weber WW, Hein DW (1985) N-acetylation pharmacogenetics. Pharmacol Rev 37:25–79PubMedPubMedCentralGoogle Scholar
  155. Wells PG et al (2004) Symposium article: glucuronidation and the UDP–glucuronosyltransferases in health and disease. Drug Metab Dispos 32:281–290PubMedCrossRefPubMedCentralGoogle Scholar
  156. Wilkinson GR (2004) Genetic variability in cytochrome P450 3A5 and in vivo cytochrome P450 3A activity: some answers but still questions. Clin Pharmacol Ther 76:99–103PubMedCrossRefPubMedCentralGoogle Scholar
  157. Wu YJ, Cheng YY, Zeng S, Ma MM (2003) Determination of dextromethorphan and its metabolite dextrorphan in human urine by capillary gas chromatography without derivatization. J Chromatogr B 784:219–224CrossRefGoogle Scholar
  158. Wusk B, Kullak-Ublick GA, Rammert C et al (2004) Thiopurine S-methyltransferase polymorphisms: efficient screening method for patients considering taking thiopurine drugs. Eur J Clin Pharmacol 60:5–10PubMedCrossRefPubMedCentralGoogle Scholar
  159. Xie HG, Kim RB, Wood AJ, Stein CM (2001) Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol 41:815–850PubMedCrossRefPubMedCentralGoogle Scholar
  160. Xie HG, Prasad HC, Kim RB, Stein CM (2002) CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev 54:1257–1270PubMedCrossRefPubMedCentralGoogle Scholar
  161. Xu C, Goodz S, Sellers E, Tyndale RF (2002) CYP2A6 genetic variation and potential consequences. Adv Drug Deliv Rev 54:1245–1256PubMedCrossRefPubMedCentralGoogle Scholar
  162. Yasar U, Dahl ML, Christensen M, Eliasson E (2002a) Intra-individual variability in urinary losartan oxidation ratio: an in vivo marker of CYP2C9 activity. Br J Clin Pharmacol 54:183–185PubMedPubMedCentralCrossRefGoogle Scholar
  163. Yasar U, Forslund-Bergengren C, Tybring G et al (2002b) Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype. Clin Pharmacol Ther 71:89–98PubMedCrossRefPubMedCentralGoogle Scholar
  164. Yasar U, Lundgren S, Eliasson E et al (2002c) Linkage between CYP2C8 and CYP2C9 genetic polymorphisms. Biochem Biophys Res Commun 299:25–28PubMedCrossRefGoogle Scholar
  165. Yim DS, Jeong JR, Park JY (2001) Assay of omeprazole and omeprazole sulfone by semi-microcolumn liquid chromatography with mixed-function precolumn. J Chromatogr B 754:487–493CrossRefGoogle Scholar
  166. Yin OQP, Tomlinson B, Chow ALH et al (2004) Omeprazole as a CYP2C19 marker in Chinese subjects: assessment of its gene-dose effect and intrasubject variability. J Clin Pharmacol 44:582–589PubMedGoogle Scholar
  167. Zanger UM, Raimindo S, Eichelbaum M (2004) Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedeberg's Arch Pharmacol 369:23–37CrossRefGoogle Scholar
  168. Zhai S, Sausville EA, Senderowicz AM et al (2003) Clinical pharmacology and pharmacogenetics of flavopiridol 1-h IV infusion in patients with refractory neoplasms. Anti-Cancer Drugs 14:125–135PubMedCrossRefGoogle Scholar
  169. Zhou S (2006) Clinical pharmacogenomics of thiopurine S-methyltransferase. Curr Clin Pharmacol 1:119–128PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.GMPK/PK Sanofi-AventisVitry-Sur-SeineFrance
  2. 2.R&D Metabolism and PK GermanySanofi Aventis Deutschland GmbHFrankfurt am MainGermany

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