Clinical Pharmacokinetics

, Volume 27, Issue 3, pp 216–248

Assessment of Liver Metabolic Function

Clinical Implications
  • Jürgen Brockmöller
  • Roots Ivar
Review Article Clinical Pharmacokinetic Concepts

Summary

Inter- and intraindividual variability in pharmacokinetics of most drugs is largely determined by variable liver function as described by parameters of hepatic blood flow and metabolic capacity. These parameters may be altered as a result of disease affecting the liver, genetic differences in metabolising enzymes, and various types of drug interactions, including enzyme induction, enzyme inhibition or down-regulation.

With the now known large number of drug metabolising enzymes, their differential substrate specificity, and their differential induction or inhibition, each test substance of liver function should be used as a probe for its specific metabolising enzyme. Thus, the concept of model test-substances providing general information about liver function has severe limitations. To test the metabolic activity of several enzymes, either several test substances may be given (cocktail approach) or several metabolites of a single test substance may be analysed (metabolic fingerprint approach). The enzyme-specific analysis of liver function results in a preference for analysis of the metabolites rather than analysis of the clearance of the parent test substance.

There are specific methods to quantify the activity of cytochrome P450 enzymes such as CYP1A2, CYP2C9, CYP2C19MEPH, CYP2D6, CYP2E1, and CYP3A, and phase II enzymes, such as glutathione S-transferases, glucuronyl-transferases or N-acetyltransferases, in vivo. Interactions based on competitive or noncompetitive inhibition should be analysed specifically for the cytochrome P450 enzyme involved. At least 5 different types of cytochrome P450 enzyme induction may result in major variability of hepatic function; this may be quantified by biochemical parameters, clearance methods, or highly enzyme-specific methods such as Western blot analysis or molecular biological techniques such as mRNA quantification in blood and tissues. Therapeutic drug monitoring is already implicitly used for quantification of the enzyme activities relevant for a specific drug.

Selective impairment of hepatic enzymes due to gene mutations may have an effect on the pharmacokinetics of certain drugs similar to that caused by cirrhosis. Assessment of this heritable source of variability in liver function is possible by in vivo or ex vivo enzymological methods. For genetically polymorphic enzymes and carrier proteins involved in drug disposition, molecular genetic methods using a patient’s blood sample may be used for classification of the individual into: (i) the impaired or poor metaboliser (homozygous deficient); (ii) the extensive (homozygous active) metaboliser group; and (iii) the moderately extensive metaboliser (heterozygous) group.

For hepatic blood flow determinations, galactose or sorbitol given at relatively low doses may be much better indicators than indocyanine green. Furthermore, theoretical pharmacokinetics of metabolites showed that quantification of a drug (with an intermediate hepatic extraction rate) and its primary metabolite after intravenous and oral administration may provide information about both the metabolic capacity and blood flow of the liver.

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References

  1. 1.
    Goldberg DM, Brown D. Advances in the application of biochemical tests to diseases of the liver and biliary tract: their role in diagnosis, prognosis, and the elucidation of pathogenic mechanisms. Clin Biochem 1987; 20: 127–84PubMedCrossRefGoogle Scholar
  2. 2.
    Johnson PJ. Role of the standard ‘liver function tests’ in current clinical practice. Ann Clin Biochem 1989; 26: 463–71PubMedGoogle Scholar
  3. 3.
    Howden CW, Birnie GG, Brodie MJ. Drug metabolism in liver disease. Pharmacol Ther 1989; 40: 439–74PubMedCrossRefGoogle Scholar
  4. 4.
    Vesell ES. The model drug approach in clinical pharmacology. Clin Pharmacol Ther 1991; 50: 239–48PubMedCrossRefGoogle Scholar
  5. 5.
    Branch RA. Drugs as indicators of hepatic function. Hepatology 1982; 2: 97–105PubMedCrossRefGoogle Scholar
  6. 6.
    Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clin Pharmacol Ther 1975; 18: 377–90PubMedGoogle Scholar
  7. 7.
    Winkler K, Bass L, Keiding S, et al. The physiologic basis for clearance measurements in hepatology. Scand J Gastroent 1979; 14: 439–48PubMedGoogle Scholar
  8. 8.
    Wilkinson GR, Branch RA. Effects of hepatic disease on clinical pharmacokinetics. In: Benet LZ, Massond N, Gambertoglio JG, editors. Pharmacokinetic basis for drug treatment. New York: Raven Press, 1984: 49–61Google Scholar
  9. 9.
    Wilkinson GR. Clearance approaches in pharmacology. Pharmacol Rev 1987; 39: 1–47PubMedGoogle Scholar
  10. 10.
    Bircher J. Quantitative assessment of deranged hepatic function: a missed opportunity? Semin Liver Dis 1983; 3: 275–84PubMedCrossRefGoogle Scholar
  11. 11.
    Guengerich FP. Separation and purification of multiple forms of microsomal cytochrome P-450. J Biol Chem 1977; 252: 3970–9PubMedGoogle Scholar
  12. 12.
    Murray M, Reidy GF. Selectivity in the inhibition of mammalian cytochrome P-450 by chemical agents. Pharmacol Rev 1990; 42: 85–101PubMedGoogle Scholar
  13. 13.
    Levin W. Functional diversity of hepatic cytochromes P-450. Drug Metab Dispos 1990; 18: 824–30PubMedGoogle Scholar
  14. 14.
    Waterman MR, Johnson EF, editors. Cytochrome P450. Methods Enzymol 1991; 206: 1–716Google Scholar
  15. 15.
    Kronbach T, Fischer V, Meyer UA. 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 1988; 43: 630–5PubMedCrossRefGoogle Scholar
  16. 16.
    Bargetzi MJ, Aoyama T, Gonzalez FJ, et al. Lidocaine metabolism in human liver microsomes by cytochrome P450IIIA4. Clin Pharmacol Ther 1989; 46: 521–7PubMedCrossRefGoogle Scholar
  17. 17.
    Kronbach T, Mathys D, Umeno M, et al. Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol 1989; 36: 89–96PubMedGoogle Scholar
  18. 18.
    Fonne-Pfister R, Meyer UA. Xenobiotic and endobiotic inhibitors of cytochrome P-450db1 function, the target of the debrisoquine/sparteine type polymorphism. Biochem Pharmacol 1988; 37: 3829–35PubMedCrossRefGoogle Scholar
  19. 19.
    Pichard L, Fabre I, Fabre H, et al. Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes. Drug Metab Dispos 1990; 18: 595–606PubMedGoogle Scholar
  20. 20.
    Fuhr U, Doehmer J, Battula N, et al. Biotransformation of caffeine and theophylline in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. Biochem Pharmacol 1992; 43: 225–35PubMedCrossRefGoogle Scholar
  21. 21.
    Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, 1992; 1–897Google Scholar
  22. 22.
    Meyer UA, Gonzalez F. Molecular genetics of the debrisoquine-sparteine polymorphism. Clin Pharmacol Ther 1991; 50: 233–8PubMedCrossRefGoogle Scholar
  23. 23.
    Bachmann KA, Nunlee M, Martin M, et al. The use of single sample clearance estimates to probe hepatic metabolism. Xenobiotica 1991; 21: 1385–92PubMedCrossRefGoogle Scholar
  24. 24.
    Bachmann KA, Jauregui L. Use of single sample clearance estimates of cytochrome P450 substrates to characterize human hepatic CYP status in vitro. Xenobiotica 1993; 23: 307–15PubMedCrossRefGoogle Scholar
  25. 25.
    Rowland M, Tozer TN. Clinical Pharmacokinetics, 2nd ed. Philadelphia: Lea & Febiger, 1989; 148–275Google Scholar
  26. 26.
    Benet LZ, Williams RL. Design and optimization of dosage regimens. In: Gilman AG, Rall TW, Nies AS, et al. editors. Goodman Gilman’s the pharmacological basis of therapeutics, 8th edition. New York: Pergamon Press, 1990: 1650–735Google Scholar
  27. 27.
    Barstow L, Small RE. Liver function assessment by drug metabolism. Pharmacotherapy 1990; 10: 280–8PubMedGoogle Scholar
  28. 28.
    Williams RL, Mamelok RD. Hepatic disease and drug pharmacokinetics. Clin Pharmacokinet 1980; 5: 528–47PubMedCrossRefGoogle Scholar
  29. 29.
    Molino G, Avagina P, Cavanna AL, et al. Sorbitol clearance: A parameter reflecting liver plasma flow in the rat. Res Commun Clin Pathol Pharmacol 1986; 52: 119–32Google Scholar
  30. 30.
    Molino G, Cavanna A, Avagnina P, et al. Hepatic clearance of D-sorbitol — noninvasive test for evaluating functional liver plasma flow. Dig Dis Sci 1987; 32: 753–8PubMedCrossRefGoogle Scholar
  31. 31.
    Zeeh J, Lange H, Bosch J, et al. Steady-state extrarenal sorbitol clearance as a measure of hepatic plasma flow. Gastroenterol 1988; 95: 749–59Google Scholar
  32. 32.
    Tygstrup N, Winkler K. Galactose blood clearance as a measure of hepatic blood flow. Clin Sci 1958; 17: 1–9PubMedGoogle Scholar
  33. 33.
    Keiding S. Hepatic clearance and liver blood flow. J Hepatol 1987; 4: 393–8PubMedCrossRefGoogle Scholar
  34. 34.
    Porchet H, Bircher J. Noninvasive assessment of portal-systemic shunting: Evaluation of a method to investigate systemic availability of oral glyceryl trinitrate by digital plethysmography. Gastroenterology 1982; 82: 629–37PubMedGoogle Scholar
  35. 35.
    Caesar J, Shaldon S, Chiandussi L, et al. The use of indocyanine green in the measurement of hepatic blood flow and as a test of hepatic function. Clin Sci 1961; 21: 43–57PubMedGoogle Scholar
  36. 36.
    Wiegand BD, Ketterer SG, Rapaport E. The use of indocyanine green for the evaluation of hepatic function and hepatic blood flow in man. Am J Dig Dis 1960; 5: 427–36PubMedCrossRefGoogle Scholar
  37. 37.
    Leevy CM, Mendenhall CL, Lesko W, et al. Estimation of hepatic blood flow with indocyanine green. J Clin Invest 1962; 41: 1169–80PubMedCrossRefGoogle Scholar
  38. 38.
    Soons PA, DeBoer A, Cohen AF, et al. Assessment of hepatic blood flow in healthy subjects by continuous infusion of indocyanine green. Br J Clin Pharmacol 1991; 32: 697–704PubMedCrossRefGoogle Scholar
  39. 39.
    Rosenthal SM, White EC. Clinical application of the bromosulphthalein test for hepatic function. JAMA 1925; 84: 112Google Scholar
  40. 40.
    Häcki W, Bircher J, Preisig R. A new look at the plasma disappearance of sulfobromophthalein (BSP): Correlation with the BSP transport maximum and the hepatic plasma flow in man. J Lab Clin Med 1976; 88: 1019–30PubMedGoogle Scholar
  41. 41.
    Leevy C, Bender J. Physiology of dye extraction by the liver: Comparative studies of sulfobromophthalein and indocyanine green. Ann NY Acad Sci 1963; 111: 161–75PubMedCrossRefGoogle Scholar
  42. 42.
    Adjepon-Yamoah KK, Nimmo J, Prescott LF. Gross impairment of hepatic drug metabolism in a patient with chronic liver disease. BMJ 1974; 4: 387–8PubMedCrossRefGoogle Scholar
  43. 43.
    Zito RA, Reid PR. Lidocaine kinetics predicted by indocyanine green clearance. N Engl J Med 1978; 298: 1160–3PubMedCrossRefGoogle Scholar
  44. 44.
    Oellerich M, Burdelski M, Lautz H-U, et al. Lidocaine metabolite formation as a measure of liver function in patients with cirrhosis. Ther Drug Monit 1990; 2: 219–26CrossRefGoogle Scholar
  45. 45.
    Branch RA, Shand DG. Propranolol disposition in chronic liver disease: A physiological approach. Clin Pharmacokinet 1976; 1: 264–79PubMedCrossRefGoogle Scholar
  46. 46.
    Kornhauser DM, Wood AJJ, Vestal RE, et al. Biological determinants of propranolol disposition in man. Clin Pharmacol Ther 1978; 23: 165–74PubMedGoogle Scholar
  47. 47.
    Henderson JM, Kutner MH, Bain RP. First-order clearance of plasma galactose: the effect of liver disease. Gastroenterology 1982; 83: 1090–6PubMedGoogle Scholar
  48. 48.
    Weber W, Looby M, Brockmöller J. Evaluation of hepatic function using the pharmacokinetics of a therapeutically administered drug — Application to the immunosuppressant cyclosporin. Clin Pharmacokinet 1992; 23: 69–83PubMedCrossRefGoogle Scholar
  49. 49.
    Weiss M. Use of metabolite AUC data in bioavailability studies to discriminate between absorption and first-pass extraction. Clin Pharmacokinet 1990; 18: 419–22PubMedCrossRefGoogle Scholar
  50. 50.
    Vesell ES. The antipyrine test in clinical pharmacology: conceptions and misconceptions. Clin Pharmacol Ther 1979; 26: 275–86PubMedGoogle Scholar
  51. 51.
    Fabre D, Bressolle F, Goméni R, et al. Identification of patients with impaired hepatic drug metabolism using a limited sampling procedure for estimation of phenazone (antipyrine) pharmacokinetic parameters. Clin Pharmacokinet 1993; 24: 333–43PubMedCrossRefGoogle Scholar
  52. 52.
    Vesell ES, Passananti GT, Glenwright PA, et al. Studies on the disposition of antipyrine, aminopyrine, and phenacetin using plasma, saliva, and urine. Clin Pharmacol Ther 1975; 18: 259–72PubMedGoogle Scholar
  53. 53.
    Døssing M, Poulsen HE, Andreasen PB, et al. A simple method for determination of antipyrine clearance. Clin Pharmacol Ther 1982; 32: 392–6PubMedCrossRefGoogle Scholar
  54. 54.
    Hepner GW, Vesell ES. Aminopyrine disposition: studies on breath, saliva and urine of normal subjects and patients with liver disease. Clin Pharmacol Ther 1976; 20: 654–60PubMedGoogle Scholar
  55. 55.
    Kawasaki S, Imamura H, Kokudo N, et al. A comparison between antipyrine and aminopyrine blood clearances. Hepato-Gastroenterol 1992; 39: 344–6Google Scholar
  56. 56.
    Wietholtz H, Zysset T, Kreiten K, et al. Effect of phenytoin, carbamazepine, and valproic acid on caffeine metabolism. Eur J Clin Pharmacol 1989; 36: 401–6PubMedCrossRefGoogle Scholar
  57. 57.
    Renner E, Wietholtz H, Huguenin P, et al. Caffeine: a model compound for measuring liver function. Hepatology 1984; 4: 38–46PubMedCrossRefGoogle Scholar
  58. 58.
    Jost G, Wahlländer A, von Mandach U, et al. Overnight salivary caffeine clearance: a liver function test suitable for routine use. Hepatology 1987; 7: 338–44.PubMedCrossRefGoogle Scholar
  59. 59.
    Scott NR, Stambuk D, Chakraborty J, et al. Caffeine clearance and biotransformation in patients with chronic liver disease. Clin Sci 1988; 74: 377–84PubMedGoogle Scholar
  60. 60.
    Zilly W, Breimer DD, Richter E. Induction of drug metabolism in man after rifampicin treatment measured by increased hexobarbital and tolbutamide clearance. Eur J Clin Pharmacol 1977; 11: 287–93PubMedCrossRefGoogle Scholar
  61. 61.
    Zilly W, Breimer DD, Richter E. Hexobarbital disposition in compensated and decompensated cirrhosis of the liver. Clin Pharmacol Ther 1978; 23: 525–34PubMedGoogle Scholar
  62. 62.
    Klotz U, Avant GR, Hoyumpa AM, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest 1975; 55: 347–59PubMedCrossRefGoogle Scholar
  63. 63.
    Andreasen PB, Hendel J, Greisen G, et al. Pharmacokinetics of diazepam in disordered liver function. Eur J Clin Pharmacol 1976; 10: 115–20PubMedCrossRefGoogle Scholar
  64. 64.
    Foberg U, Broström C, Freyden A, et al. Evaluation of an oral bile acid loading test for assessment of liver function in chronic hepatitis. Liver 1987; 7: 116–22PubMedGoogle Scholar
  65. 65.
    Van Waeg G, Lööf L, Groth T, et al. Allopurinol kinetics in humans as a means to assess liver function: evaluation of an allopurinol loading test. Scand J Clin Lab Invest 1988; 48: 45–57PubMedGoogle Scholar
  66. 66.
    Toverud EL, Boobis AR, Brodie MJ, et al. Differential induction of antipyrine metabolism by rifampicin. Eur J Clin Pharmacol 1982; 21: 155–60CrossRefGoogle Scholar
  67. 67.
    Danhof M, van Zuilen A, Boeijinga JK, et al. Studies of the different metabolic pathways of antipyrine in man. Eur J Clin Pharmacol 1982; 21: 433–41PubMedCrossRefGoogle Scholar
  68. 68.
    Teunissen MWE, Kampf D, Roots I, et al. Antipyrine metabolite formation and excretion in patients with chronic renal failure. Eur J Clin Pharmacol 1985; 28: 589–95PubMedCrossRefGoogle Scholar
  69. 69.
    Conney AH, Pantuck EJ, Kuntzman R, et al. Nutrition and chemical biotransformation in man. Clin Pharmacol Ther 1977; 22: 707–20PubMedGoogle Scholar
  70. 70.
    Carrum G, Egan JM, Abernethy DR. Diltiazem treatment impairs hepatic drug oxidation: studies on antipyrine. Clin Pharmacol Ther 1986; 40: 140–3PubMedCrossRefGoogle Scholar
  71. 71.
    Pichard L, Gillet G, Fabre I, et al. Identification of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the N-demethylation of diltiazem. Drug Metab Dispos 1990; 18: 711–8PubMedGoogle Scholar
  72. 72.
    Danhof M, Verbeek RMA, van Boxtel CJ, et al. Differential effects of enzyme induction on antipyrine metabolite formation. Br J Clin Pharmacol 1982; 13: 379–86PubMedCrossRefGoogle Scholar
  73. 73.
    Gu L, Gonzalez FJ, Kalow W, et al. Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics 1992; 2: 73–7PubMedCrossRefGoogle Scholar
  74. 74.
    Bertilsson L, Henthorn TK, Sanz E, et al. Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquine, hydroxylation phenotype. Clin Pharmacol Ther 1989; 45: 348–55PubMedCrossRefGoogle Scholar
  75. 75.
    Lown K, Kolars J, Turgeon K, et al. The erythromycin breath test selectively measures P450IIIA in patients with severe liver disease. Clin Pharmacol Ther 1992; 51: 229–38PubMedCrossRefGoogle Scholar
  76. 76.
    Goresky CA, Bach GG, Nadeau BE. On the uptake of material by the intact liver: the transport and net removal of galactose. J Clin Invest 1973; 52: 991–1009PubMedCrossRefGoogle Scholar
  77. 77.
    Yasumori T, Murayama N, Yamazoe Y, et al. Polymorphism in hydroxylation of mephenytoin and hexobarbital stereoisomers in relation to hepatic P-450 human-2. Clin Pharmacol Ther 1990; 47: 313–22PubMedCrossRefGoogle Scholar
  78. 78.
    Zilly W, Breimer DD, Richter E. Hexobarbital disposition in compensated and decompensated cirrhosis of the liver. Clin Pharmacol Ther 1978; 23: 525–34PubMedGoogle Scholar
  79. 79.
    Greenblatt DJ, Allen MD, Locniskar A, et al. Lorazepam kinetics in the elderly. Clin Pharamacol Ther 1979; 26: 103–13Google Scholar
  80. 80.
    Boobis AR, Fawthrop DJ, Seddon CE, et al. Variability in the pharmacokinetics and metabolism of acetaminophen. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, 1992: 791–812Google Scholar
  81. 81.
    Ward SA, Walle T, Walle UK, et al. Propranolol’s metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities. Clin Pharmacol Ther 1989; 45: 72–9PubMedCrossRefGoogle Scholar
  82. 82.
    Butler MA, Iwasaki M, Guengerich FP, et al. Human cytochrome P-450PA (P4501A2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proc Natl Acad Sci USA 1989; 86: 7696–700PubMedCrossRefGoogle Scholar
  83. 83.
    Tassaneeyakul W, Veronese ME, Birkett DJ, et al. Co-regulation of phenytoin and tolbutamide metabolism in humans. Br J Clin Pharmacol 1992; 34: 494–8PubMedGoogle Scholar
  84. 84.
    Nelson DW, Kamataki T, Waxman DJ, et al. The P450 super-family: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 1993; 12: 1–51PubMedCrossRefGoogle Scholar
  85. 85.
    Nebert DW, Adesnik M, Coon MJ, et al. The P450 gene super-family: recommended nomenclature. DNA Cell Biol 1987; 6: 1–11CrossRefGoogle Scholar
  86. 86.
    Nebert DW, Gonzalez FJ. P450 genes: structure, evolution, and regulation. Annu Rev Biochem 1987; 56: 945–93PubMedCrossRefGoogle Scholar
  87. 87.
    Gonzalez FJ. Human cytochromes P450: problems and prospects. Trends Pharmacol Sci 1992; 13: 346–52PubMedCrossRefGoogle Scholar
  88. 88.
    Guengerich FP. Characterization of human microsomal cytochrome P-450 enzymes. Annu Rev Pharmacol Toxicol 1989; 29: 241–64PubMedCrossRefGoogle Scholar
  89. 89.
    Bircher J. Assessment of prognosis in advanced liver disease: to score or to measure, that’s the question. Hepatology 1986; 6: 1036–7PubMedCrossRefGoogle Scholar
  90. 90.
    Albers I, Hartmann H, Bircher J, et al. Superiority of the Child-Pough classification to quantitative liver function tests for assessing prognosis of liver cirrhosis. Scand J Gastroenterol 1989; 24: 269–76PubMedCrossRefGoogle Scholar
  91. 91.
    St Peter JV, Awni WM. Quantifying hepatic function in the presence of liver disease with phenazone (antipyrine) and its metabolites. Clin Pharmacokinet 1991; 20: 50–65PubMedCrossRefGoogle Scholar
  92. 92.
    Hartleb M. Drugs and the liver. Part II, The role of the antipyrine test in drug metabolism studies. Biopharm Drug Dispos 1991; 12: 559–70PubMedCrossRefGoogle Scholar
  93. 93.
    Poulsen HE, Loft S. Antipyrine as a model drug to study hepatic drug-metabolizing capacity. J Hepatol 1988; 6: 374–82PubMedCrossRefGoogle Scholar
  94. 94.
    Penno MB, Vesell ES. Monogenic control of variations in antipyrine metabolite formation — New polymorphism of hepatic drug oxidation. J Clin Invest 1983; 71: 1698–709PubMedCrossRefGoogle Scholar
  95. 95.
    Pazzucconi F, Malavasi B, Galli G, et al. Inhibition of antipyrine metabolism by low-dose contraceptives with gestodene and desogestrel. Clin Pharmacol Ther 1991; 49: 278–84PubMedCrossRefGoogle Scholar
  96. 96.
    Andersson T. Omeprazole drug interaction studies. Clin Pharmacokinet 1991; 21: 195–212PubMedCrossRefGoogle Scholar
  97. 97.
    Andersson T, Miners JO, Veronese ME, et al. Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol 1993; 36: 521–30PubMedCrossRefGoogle Scholar
  98. 98.
    Guengerich FP, editor. Mammalian cytochromes P-450, Vol 1. Boca Raton, Florida: CRC Press, 1987; 133–98Google Scholar
  99. 99.
    Watkins PB. Role of cytochromes P450 in drug metabolism and hepatotoxicity. Semin Liver Dis 1990; 10: 235–50PubMedCrossRefGoogle Scholar
  100. 100.
    Guengerich FP. Characterization of human cytochrome P450 enzymes. FASEB J 1992; 6: 745–8PubMedGoogle Scholar
  101. 101.
    Murray M. P450 Enzymes inhibition: mechanisms, genetic regulation and effects of liver disease. Clin Pharmacokinet 1992; 23: 132–46PubMedCrossRefGoogle Scholar
  102. 102.
    Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol 1992; 22: 1–21PubMedCrossRefGoogle Scholar
  103. 103.
    Caporaso NE, Shaw GL. Clinical implications of the competitive inhibition of the debrisoquine-metabolizing isoenzyme by quinidine. Ann Intern Med 1991; 151: 1985–91CrossRefGoogle Scholar
  104. 104.
    Gonzalez FJ, Idle J. Pharmacogenetic phenotyping and genotyping: present status and future potential. Clin Pharmacokinet 1994; 26: 59–70PubMedCrossRefGoogle Scholar
  105. 105.
    Birkett DJ, Mackenzie PI, Veronese ME, et al. In vitro approaches can predict human drug metabolism. Trends Pharmacol Sci 1993; 14: 292–4CrossRefGoogle Scholar
  106. 106.
    Cheng WCS, Murphy TL, Smith MT, et al. Dose-dependent pharmacokinetics of caffeine in humans: relevance as a test of quantitative liver function. Clin Pharmacol Ther 1990; 47: 516–24PubMedCrossRefGoogle Scholar
  107. 107.
    Parsons WD, Neims AH. Effect of smoking on caffeine clearance. Clin Pharmacol Ther 1978; 24: 40–5PubMedGoogle Scholar
  108. 108.
    Kalow W, Tang BK. The use of caffeine for enzyme assays: a critical appraisal. Clin Pharmacol Ther 1993; 53: 503–14PubMedCrossRefGoogle Scholar
  109. 109.
    Tassaneeyakul W, Birkett DJ, McManus ME, et al. Caffeine metabolism by human hepatic cytochromes P450: contributions of 1A1, 2E1 and 3A isoforms. Biochem Pharmacol 1994; 47: 1767–1776PubMedCrossRefGoogle Scholar
  110. 110.
    Campbell ME, Spielberg SP, Kalow W. A urinary metabolic ratio that reflects systemic caffeine clearance. Clin Pharmacol Ther 1987; 42: 157–65PubMedCrossRefGoogle Scholar
  111. 111.
    Kalow W, Tang BK. Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther 1991; 50: 508–19PubMedCrossRefGoogle Scholar
  112. 112.
    Lelo A, Miners JO, Robson RA, et al. Quantitative assessment of caffeine partial clearances in man. Br J Clin Pharmacol 1986; 22: 183–6PubMedCrossRefGoogle Scholar
  113. 113.
    Kalow W, Tang BK. Caffeine as a metabolic probe: Exploration of the enzyme-inducing effect of cigarette smoking. Clin Pharmacol Ther 1991; 49: 44–8PubMedCrossRefGoogle Scholar
  114. 114.
    Butler MA, Lang NP, Young JF, et al. Determination of CAP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites. Pharmacogenetics 1992; 2: 116–27PubMedCrossRefGoogle Scholar
  115. 115.
    Relling MV, Lin J-S, Ayers GD, et al. Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin Pharmacol Ther 1992; 52: 643–58PubMedCrossRefGoogle Scholar
  116. 116.
    Rost KL, Roots I. Accelerated caffeine metabolism after omeprazole treatment is indicated by urinary metabolite ratios — coincidence with plasma clearance and breath test. Clin Pharmacol Ther 1994; 55: 402–11PubMedCrossRefGoogle Scholar
  117. 117.
    Grant DM, Tang BK, Kalow W. A simple test for acetylator phenotype using caffeine. Br J Clin Pharmacol 1984; 17: 459–64PubMedCrossRefGoogle Scholar
  118. 118.
    Tang BK, Kadar DM, Kalow W. An alternative test for acetylator phenotyping with caffeine. Clin Pharmacol Ther 1987; 42: 509–13PubMedCrossRefGoogle Scholar
  119. 119.
    Tang BK, Kadar K, Qian L, et al. Caffeine as a metabolic probe: Validation of its use for acetylator phenotyping. Clin Pharmacol Ther 1991; 49: 648–57PubMedCrossRefGoogle Scholar
  120. 120.
    Bechtel YC, Bonaiti-Pellic C, Poisson N, et al. A population and family study of N-acetyltransferase using caffeine urinary metabolites. Clin Pharmacol Ther 1993; 54: 134–41PubMedCrossRefGoogle Scholar
  121. 121.
    Guerciolini R, Szumlanski C, Weinshilboum RM. Human liver xanthine oxidase: nature and extent of individual variation. Clin Pharmacol Ther 1991; 50: 663–7PubMedCrossRefGoogle Scholar
  122. 122.
    Kaminsky LS, Dunbar DA, Wang PP, et al. Human hepatic cytochrome P-450 composition as probed by in vitro microsomal metabolism of warfarin. Drug Metab Dispos 1984; 12: 470–7PubMedGoogle Scholar
  123. 123.
    Rettie AE, Eddy AC, Heimark LD, et al. Characteristics of warfarin hydroxylation catalysed by human liver microsomes. Drug Metab Dispos 1989; 17: 265–70PubMedGoogle Scholar
  124. 124.
    Forrest JAH, Finlayson NDC, Adjepon-Yamoah KK, et al. Antipyrine, paracetamol, and lignocaine elimination in chronic liver disease. BMJ 1977; 1: 1384–7PubMedCrossRefGoogle Scholar
  125. 125.
    Oellerich M, Burdelski M, Lautz HU, et al. Assessment of pretransplant prognosis in patients with cirrhosis. Transplantation 1991; 51: 801–6PubMedCrossRefGoogle Scholar
  126. 126.
    Oellerich M, Burdelski M, Lautz HU, et al. Predictors of one-year pretransplant survival in patients with cirrhosis. Hepatology 1991; 14: 1029–34PubMedCrossRefGoogle Scholar
  127. 127.
    Burdelski M, Oellerich P, Lamesch P, et al. Evaluation of quantitative liver function tests in liver donors. Transplant Proc 1987; 19: 3838–9PubMedGoogle Scholar
  128. 128.
    Thomson AJ, Elliott HL, Kelman AW, et al. The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects. J Pharmacokinet Biopharm 1987; 15: 101–15PubMedGoogle Scholar
  129. 129.
    Colli A, Buccino G, Cocciolo M, et al. Disposition of a flow-limited drug (lidocaine) and a metabolic capacity-limited drug (theophylline) in liver cirrhosis. Clin Pharmacol Ther 1988; 44: 642–9PubMedCrossRefGoogle Scholar
  130. 130.
    Pomier-Layrargues G, Huet PM, Infante-Pivard C, et al. Prognostic value of indocyanine green and lidocaine kinetics for survival and chronic hepatic encephalopathy in cirrhotic patients following elective end-to-side portocaval shunt. Hepatology 1988; 8: 1506–10PubMedCrossRefGoogle Scholar
  131. 131.
    Watkins PB, Hamilton TA, Annesley TM, et al. The erythromycin breath test as a predictor of cyclosporine blood levels. Clin Pharmacol Ther 1990; 48: 120–9PubMedCrossRefGoogle Scholar
  132. 132.
    Hunt CM, Watkins PB, Saenger P, et al. Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol. Clin Pharmacol Ther 1992; 51: 18–23PubMedCrossRefGoogle Scholar
  133. 133.
    May DG, Porter J, Wilkinson GR, et al. Frequency distribution of dapsone N-hydroxylase, a putative probe for P4503A4 activity, in a white population. Clin Pharmacol Ther 1994; 55: 492–500PubMedCrossRefGoogle Scholar
  134. 134.
    Kumar GN, Walle UK, Walle T. Cytochrome P450 3A-mediated human liver microsomal taxol 6α-hydroxylation. J Pharmacol Exp Ther 1994; 268: 1160–5PubMedGoogle Scholar
  135. 135.
    Shimada T, Iwasaki M, Martin MV, et al. Human liver microsomal cytochrome P-450 enzymes involved in the bioactivation of procarcinogens detected by umu gene response in Salmonella typhimurium TA 1535/pSK1002. Cancer Res 1989; 49: 3218–28PubMedGoogle Scholar
  136. 136.
    Reiss WG, Bauer LA, Horn JR, et al. The effects of oral nifedipine on hepatic blood flow in humans. Clin Pharmacol Ther 1991; 50: 379–84PubMedCrossRefGoogle Scholar
  137. 137.
    Wrighton SA, Ring BJ, Watkins PB, et al. Identification of a polymorphically expressed member of the human cytochrome P-450III family. Mol Pharmacol 1989; 36: 97–105PubMedGoogle Scholar
  138. 138.
    Aoyama T, Yamano S, Waxman DJ, et al. Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. J Biol Chem 1989; 264: 10388–95PubMedGoogle Scholar
  139. 139.
    Kleinbloesem CH, van Brummelen P, Faber H, et al. Variability in nifedipine pharmacokinetics and dynamics: a new oxidation polymorphism in man. Biochem Pharmacol 1984; 33: 3721–4PubMedCrossRefGoogle Scholar
  140. 140.
    Schellens JHM, Soons PA, Breimer DD. Lack of bimodality in nifedipine plasma kinetics in a large population of healthy subjects. Biochem Pharmacol 1988; 37: 2507–10PubMedCrossRefGoogle Scholar
  141. 141.
    Breimer DD, Schellens JHM. A ‘cocktail’ strategy to assess in vivo oxidative drug metabolism in humans. Trends Pharmacol Sci 1990; 11: 223–5PubMedCrossRefGoogle Scholar
  142. 142.
    Breimer DD. Potential clinical relevance of the interplay between genetic and environmental factors. In: Alvan G, Balant LP, Bechtel PR, et al. editors. COST B1: European consensus conference on pharmacogenetics. Brussels: Publications of the European Community, 1990: 69–80Google Scholar
  143. 143.
    Jacqz-Aigrain E, Funck-Brentano C, Cresteil T. CYP2D6- and CYP3A-dependent metabolism of dextromethorphan in humans. Pharmacogenetics 1993; 3: 197–204PubMedCrossRefGoogle Scholar
  144. 144.
    Crom WR, Webster SL, Bobo L, et al. Simultaneous administration of multiple model substrates to assess hepatic drug clearance. Clin Pharmacol Ther 1987; 41: 645–50PubMedCrossRefGoogle Scholar
  145. 145.
    Relling MV, Crom WR, Pieper JA, et al. Hepatic drug clearance in children with leukemia: changes in clearance of model substrates during remission-induction therapy. Clin Pharmacol Ther 1987; 41: 651–60PubMedCrossRefGoogle Scholar
  146. 146.
    Boucher BA, Kuhl DA, Fabian TC, et al. Effect of neurotrauma on hepatic drug clearance. Clin Pharmacol Ther 1991; 50: 487–97PubMedCrossRefGoogle Scholar
  147. 147.
    Back DJ, Tija J, Mönig H, et al. Selective inhibition of drug oxidation after simultaneous administration of two probe drugs, antipyrine and tolbutamide. Eur J Clin Pharmacol 1988; 34: 157–63PubMedCrossRefGoogle Scholar
  148. 148.
    Schellens JHM, Van der Wart JHF, Danhof M, et al. Relationship between the metabolism of antipyrine, hexobarbitone and theophylline in man as assessed by a ‘cocktail’ approach. Br J Clin Pharmacol 1988; 26: 373–84PubMedCrossRefGoogle Scholar
  149. 149.
    Loft S. Metronidazole and antipyrine as probes for the study of foreign compound metabolism. Pharmacol Toxicol 1990; 66 Suppl.6: 1–31PubMedCrossRefGoogle Scholar
  150. 150.
    Schellens JHM, van der Wart JHF, Brugman M, et al. Influence of enzyme induction on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in humans as assessed by a ‘cocktail’ study design. J Pharmacol Exp Ther 1989; 249: 638–45PubMedGoogle Scholar
  151. 151.
    Schellens JHM, Ghabrial H, van der Wart JHF, et al. Differential effects of quinidine on the disposition of nifedipine, sparteine, and mephenytoin in humans. Clin Pharmacol Ther 1991; 50: 520–8PubMedCrossRefGoogle Scholar
  152. 152.
    Evans WE, Relling MV, Petros WP, et al. Dextromethorphan and caffeine as probes for simultaneous determination of debrisoquin-oxidation and N-acetylation phenotypes in children. Clin Pharmacol Ther 1989; 45: 568–73PubMedCrossRefGoogle Scholar
  153. 153.
    Guttendorf RJ, Britto M, Blouin RA, et al. Rapid screening for polymorphism in dextromethorphan and mephenytoin metabolism. Br J Clin Pharmacol 1990; 29: 373–80PubMedCrossRefGoogle Scholar
  154. 154.
    Sanz EJ, Villén T, Alm C, et al. S-Mephenytoin hydroxylation phenotypes in a Swedish population determined after coadministration with debrisoquine. Clin Pharmacol Ther 1989; 45: 495–9PubMedCrossRefGoogle Scholar
  155. 155.
    Hoyumpa AM, Schenker S. Is glucuronidation truly preserved in patients with liver disease? Hepatology 1991; 13: 786–95PubMedCrossRefGoogle Scholar
  156. 156.
    Miners JO, Mackenzie PI. Drug glucuronidation in humans. Pharmacol Ther 1991; 51: 347–69PubMedCrossRefGoogle Scholar
  157. 157.
    Burchell B, Nebert DW, Nelson DR, et al. The UDP glucuronosyltransferase gene superfamily: Suggested nomenclature based on evolutionary divergence. DNA Cell Biol 1991; 10: 487–94PubMedCrossRefGoogle Scholar
  158. 158.
    Tephly TR, Burchell B. UDP-glucuronosyltransferases: A family of detoxifying enzymes. Trends Pharmacol Sci 1990; 11: 276–9PubMedCrossRefGoogle Scholar
  159. 159.
    Angus PW, Mihaly GW, Morgan DJ, et al. Oxygen dependence of salbutamol elimination by the isolated perfused rat liver. Biochem Pharmacol 1989; 38: 1443–9PubMedCrossRefGoogle Scholar
  160. 160.
    Herman RJ, Duc Van Pham J, Szakacs CBN. Disposition of lorazepam in human beings: enterohepatic recirculation and first pass effect. Clin Pharmacol Ther 1989; 46: 18–25PubMedCrossRefGoogle Scholar
  161. 161.
    Baker AL, Kotake AN, Schoeller DA. Clinical utility of breath tests for the assessment of hepatic function. Semin Liver Dis 1983; 3: 318–29PubMedCrossRefGoogle Scholar
  162. 162.
    Bircher J, Preisig R. Exhalation of isotopic CO2. Methods Enzymol 1981; 77: 3–9PubMedCrossRefGoogle Scholar
  163. 163.
    Lane EA, Parashos I. Drug pharmacokinetics and the carbon dioxide breath test. J Pharmacokinet Biopharm 1986; 14: 29–49PubMedGoogle Scholar
  164. 164.
    Hepner GW, Vesell ES. Assessment of aminopyrine metabolism in man by breath analysis after oral administration of 14C-aminopyrine. Effects of phenobarbital, disulfiram, and portal cirrhosis. N Engl J Med 1974; 291: 1384–8PubMedCrossRefGoogle Scholar
  165. 165.
    Roots I, Nigam S, Gramatzki S, et al. Hybrid information provided by the 14C-aminopyrine breath test. Studies with 14C-monomethylaminoantipyrine in the guinea pig. Naunyn-Schmiedeberg’s Arch Pharmacol 1980; 313: 175–8CrossRefGoogle Scholar
  166. 166.
    Arnaud MJ, Thelin-Doerner A, Ravussin E, et al. Study of the demethylation of (1, 3, 7-methyl 13C) caffeine in man using respiratory exchange measurements. Biomed Mass Spectrom 1980; 7: 521–4PubMedCrossRefGoogle Scholar
  167. 167.
    Wietholtz H, Voegelin M, Arnaud MJ, et al. Assessment of the cytochrome P-448 dependent liver enzyme system by a caffeine breath test. Eur J Clin Pharmacol 1981; 21: 53–9PubMedCrossRefGoogle Scholar
  168. 168.
    Kotake AN, Schoeller DA, Lambert GH, et al. The caffeine CO2 breath test: dose response and route of N-demethylation in smokers and nonsmokers. Clin Pharmacol Ther 1982; 32: 261–9PubMedCrossRefGoogle Scholar
  169. 169.
    Rost KL, Brösicke H, Brockmöller J, et al. Increase of cytochrome P450IA2 activity by omeprazole: Evidence by the 13C-[N-3-methyl]-caffeine breath test in poor and extensive metabolizers of S-mephenytoin. Clin Pharmacol Ther 1992; 52: 170–80PubMedCrossRefGoogle Scholar
  170. 170.
    Hepner GW, Vesell ES, Lipton A, et al. Disposition of aminopyrine, antipyrine, diazepam, and indocyanine green in patients with liver disease or on anticonvulsant drug therapy: Diazepam breath test and correlations in drug elimination. J Lab Clin Med 1977; 90: 440–56PubMedGoogle Scholar
  171. 171.
    Shreeve WW, Shoop JD, Ott DG, et al. Test for alcoholic cirrhosis by conversion of [14C]- or [13C]-galactose to expired CO2. Gastroenterology 1976; 71: 98–101PubMedGoogle Scholar
  172. 172.
    Grimm L, Bircher J, Preisig R. Der Galaktose-Atemtest. Z Gastroenterol 1980; 18: 45–56PubMedGoogle Scholar
  173. 173.
    Krumbiegel P, Günther K, Faust H, et al. Nuclear medicine liver function tests for pregnant women and children 1. Breath tests with 14C-methacetin and 13C-methacetin. Eur J Nucl Med 1985; 10: 129–33PubMedCrossRefGoogle Scholar
  174. 174.
    Schoeller DA, Kotake AN, Lambert GH, et al. Comparison of the phenacetin and aminopyrine breath tests: effects of liver disease, inducers and cobaltous chloride. Hepatology 1985; 5: 276–81PubMedCrossRefGoogle Scholar
  175. 175.
    Watkins PB, Murray SA, Winkelman LG, et al. Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. J Clin Invest 1989; 83: 688–97PubMedCrossRefGoogle Scholar
  176. 176.
    Watkins PB, Turgeon DK, Saenger P, et al. Comparison of urinary 6β-cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity. Clin Pharmacol Ther 1992; 52: 265–73PubMedCrossRefGoogle Scholar
  177. 177.
    Craig PI, Tapner M, Farrell GC. Interferon suppresses erythromycin metabolism in rats and human subjects. Hepatology 1993; 17: 230–5PubMedCrossRefGoogle Scholar
  178. 178.
    Rautio A, Kraul H, Kojo A, et al. Interindividual variability of coumarin 7-hydroxylation in healthy volunteers. Pharmacogenetics 1992; 2: 227–33PubMedCrossRefGoogle Scholar
  179. 179.
    Lennard MS, Silas JH, Smith AJ, et al. Determination of debrisoquine and its 4-hydroxy metabolite in biological fluids by gas chromatography with flame-ionisation and nitrogen-selective detection. J Chromatogr 1977; 133: 161–6PubMedCrossRefGoogle Scholar
  180. 180.
    Steiner E, Bertilsson L, Säwe J, et al. Polymorphic debrisoquin hydroxylation in 757 Swedish subjects. Clin Pharmacol Ther 1988; 44: 431–5PubMedCrossRefGoogle Scholar
  181. 181.
    Roots I, Drakoulis N, Ploch M, et al. Debrisoquine hydroxylation phenotype, acetylation phenotype, and ABO blood groups as genetic host factors of lung cancer risk. Klin Wochenschr 1988: 66 Suppl. 11; 87–97PubMedGoogle Scholar
  182. 182.
    Schmid B, Bircher J, Preisig R, et al. Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquine hydroxylation. Clin Pharmacol Ther 1985; 38: 618–24PubMedCrossRefGoogle Scholar
  183. 183.
    Eichelbaum M, Spannbrucker N, Dengler HJ. Influence of the defective metabolism of sparteine on its pharmacokinetics. Eur J Clin Pharmacol 1979; 16: 189–94PubMedCrossRefGoogle Scholar
  184. 184.
    Wedlund PJ, Aslanian WS, McAllister CB, et al. Mephenytoin hydroxylation deficiency in Caucasians: Frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 1984; 36: 773–80PubMedCrossRefGoogle Scholar
  185. 185.
    Meier UT, Dayer P, Malè PJ, et al. Mephenytoin hydroxylation polymorphism: Characterization of the enzymatic deficiency in liver microsomes of poor metabolizers phenotypes in vivo. Clin Pharmacol Ther 1985; 38: 488–94PubMedCrossRefGoogle Scholar
  186. 186.
    Rost KL, Brockmöller J, Esdorn F, et al. Phenotyping of CYP2C19(Meph) by omeprazole during multiple-dose treatment of healthy volunteers and hospital patients. Clin Pharmacol Ther. Submitted for publicationGoogle Scholar
  187. 187.
    Conney AH, Burns JJ. Physiological disposition and metabolic fate of chlorzoxazone (Paraflex) in man. J Pharmacol Exp Ther 1960; 128: 340–3PubMedGoogle Scholar
  188. 188.
    Peter R, Böcker R, Beaune PH, et al. Hydroxylation of chlorzoxazone as a specific probe for human liver cytochrome P-450 IIE1. Chem Res Toxicol 1990; 3: 566–73PubMedCrossRefGoogle Scholar
  189. 189.
    Kharasch ED, Thummel KE, Mhyre J, et al. Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1. Clin Pharmacol Ther 1993; 53: 643–50PubMedCrossRefGoogle Scholar
  190. 190.
    Carriere V, Goasduff T, Ratanasavanh D, et al. Both cytochromes P450 2E1 and 1A1 are involved in the metabolism of chlorzoxazone. Chem Res Toxicol 1993; 6: 852–7PubMedCrossRefGoogle Scholar
  191. 191.
    Bock KW, Wiltfang J, Blume R, et al. Paracetamol as a test drug to determine glucuronide formation in man. Effects of inducers and of smoking. Eur J Clin Pharmacol 1987; 31: 677–83PubMedCrossRefGoogle Scholar
  192. 192.
    Abernethy DR, Greenblatt DJ, Ameer B, et al. Probenecid impairment of acetaminophen and loracepam clearance: direct inhibition of ether glucuronide formation. J Pharmacol Exp Ther 1985; 234: 345–9PubMedGoogle Scholar
  193. 193.
    Kroetz DL, Kerr BM, McFarland LV, et al. Measurement of in vivo microsomal epoxide hydrolase activity in white subjects. Clin Pharmacol Ther 1993; 53: 306–15PubMedCrossRefGoogle Scholar
  194. 194.
    Carr K, Oates JA, Nies AS, et al. Simultaneous analysis of dapsone and monoacetyldapsone employing high performance liquid chromatography: a rapid method for determination of acetylator phenotype. Br J Clin Pharmacol 1978; 6: 421–7PubMedCrossRefGoogle Scholar
  195. 195.
    May DG, Arns PA, Richards WO, et al. The disposition of dapsone in cirrhosis. Clin Pharmacol Ther 1992; 51: 689–700PubMedCrossRefGoogle Scholar
  196. 196.
    Hutchings A, Routledge PA. A simple method for determining acetylator phenotype using isoniazid. Br J Clin Pharmacol 1986; 22: 343–5PubMedCrossRefGoogle Scholar
  197. 197.
    Inaba T, Arias TD. On phenotyping with isoniazid: the use of urinary acetylation ratio and the uniqueness of antimodes. Study of two Amerindian populations. Clin Pharmacol Ther 1987; 42: 493–7PubMedCrossRefGoogle Scholar
  198. 198.
    Evans DAP. An improved and simplified method of detecting acetylator phenotype. J Med Genet 1969; 6: 405–7PubMedCrossRefGoogle Scholar
  199. 199.
    Weber WW. The acetylator genes and drug response. New York: Oxford University Press, 1987Google Scholar
  200. 200.
    Seidegard J, De Pierre JW, Birberg W, et al. Characterization of soluble glutathione transferase activity in resting mononuclear leukocytes from human blood. Biochem Pharmacol 198; 433: 3053–8Google Scholar
  201. 201.
    Brockmöller J, Gross D, Kerb R, et al. Correlation between trans-stilbene oxide-glutathione conjugation activity and the deletion mutation in the glutathione S-transferase class Mu gene detected by polymerase chain reaction. Biochem Pharmacol 1992; 43: 647–50PubMedCrossRefGoogle Scholar
  202. 202.
    Gill SS, Ota K, Hammock BD. Radiometric assays for mammalian epoxide hydrolases and glutathione S-transferase. Anal Biochem 1983; 131: 273–82PubMedCrossRefGoogle Scholar
  203. 203.
    Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. J Hum Genet 1980; 32: 651–62Google Scholar
  204. 204.
    Honchel R, Aksoy IA, Szumlanski C, et al. Human thiopurine methyltransferase: Molecular cloning and expression of T84 colon carcinoma cell cDNA. Mol Pharmacol 1993; 43: 878–87PubMedGoogle Scholar
  205. 205.
    Lennard L, Lilleyman JS, Van Loon J, et al. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 1990; 336: 225–9PubMedCrossRefGoogle Scholar
  206. 206.
    Keith RA, Jardine I, Kerremans A, et al. Human erythrocyte membrane thiol methyltransferase: S-methylation of captopril, N-acetylcysteine and 7-α-thio-spirolactone. Drug Metab Dispos 1984; 12: 717–24PubMedGoogle Scholar
  207. 207.
    Sundaram R, van Loon JA, Tucker R, et al. Sulfation pharmacogenetics: correlation of human platelet and small intestinal phenol sulfotransferase. Clin Pharmacol Ther 1989; 46: 501–9PubMedCrossRefGoogle Scholar
  208. 208.
    Pink JC, Messing EM, Reznikoff CA, et al. Correlation between N-acetyltransferase activities in uroepithelia and in vivo acetylator phenotype. Drug Metab Dispos 1992; 20: 559–65PubMedGoogle Scholar
  209. 209.
    Grant DM. Molecular genetics of the N-acetyltransferases. Pharmacogenetics 1993; 3: 45–50PubMedCrossRefGoogle Scholar
  210. 210.
    Ferguson RJ, Doll MA, Rustan TD, et al. Cloning, expression and functional characterization of two mutant (NAT2191 and NAT2341/803) and wild-type human polymorphic N-acetyltransferase (NAT2) alleles. Drug Metab Dispos 1994; 22: 371–6PubMedGoogle Scholar
  211. 211.
    Brockmöller J, Kerb R, Drakoulis N, et al. Gluathionse S-transferase M1 and its variants A and B as host factors of bladder cancer susceptibility: a case control study. Cancer Res 1994; 54: 4103–11PubMedGoogle Scholar
  212. 212.
    Heim M, Meyer UA. Genotyping of poor metabolizers of debrisoquine by allele-specific PCR amplification. Lancet 1990; 336: 529–32PubMedCrossRefGoogle Scholar
  213. 213.
    de Morais SMF, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994; 269: 15419–22PubMedGoogle Scholar
  214. 214.
    Dayer P. Advantages and drawbacks of probe drugs for the assessment of phenotypic expression of cytochrom P450db1 (P450IID6). In: Alvan G, Balant LP, Bechtel PR, et al. editors. COST B1: European consensus conference on pharmacogenetics. Brussels: Publications of the European Community, 1990: 33–42Google Scholar
  215. 215.
    Bechtel PR, Bechtel Y. N-Acetyltransferase. In: Alvan G, Balant LP, Bechtel PR, et al. editors. COST B1: European consensus conference on pharmacogenetics. Brussels: Publications of the European Community, 1990: 161–9Google Scholar
  216. 216.
    Reidenberg MM. Potential artifacts in the use of caffeine to determine acetylation phenotype. Br J Clin Pharmacol 1989; 28: 207–8PubMedCrossRefGoogle Scholar
  217. 217.
    Travers AF. A fatality after antipyrine administration. Clin Pharmacol Ther 1991; 49: 695–6PubMedCrossRefGoogle Scholar
  218. 218.
    Herd B, Wynne H, Wright P, et al. The effect of age on glucuronidation and sulfation of paracetamol by human liver fractions. Br J Clin Pharmacol 1991; 32: 768–70PubMedGoogle Scholar
  219. 219.
    Zand R, Nelson SD, Slattery JT, et al. Inhibition and induction of cytochrome P4502E1-catalysed oxidation by isoniazid in humans. Clin Pharmacol Ther 1993; 54: 142–9PubMedCrossRefGoogle Scholar
  220. 220.
    Windorfer A, Jurkat C. Arzeimittel im Strassenverkehr, Stuttgard: Wissenschaftliche Verlagsgesellschaft, 1991: 63–77Google Scholar
  221. 221.
    Gitzelmann R, Steinmann B, von den Berghe G. Disorders of fructose metabolism. In: Scriver CR, Beaudet AL, Sly WS, et al., editors. The metabolic basis of inherited disease, 6th edition. New York: McGraw-Hill, 1989: 399–424Google Scholar
  222. 222.
    Ruiz del Arbol L, García-Pagán J-C, Feu F, et al. Indocyaninegreen: Infusion rate and reactions. Ann Intern Med 1989; 110: 844–5PubMedGoogle Scholar
  223. 223.
    Speich R, Saesseli B, Hoffmann U, et al. Anaphylactoid reactions after indocyanine-green administration. Ann Intern Med 1988; 109: 345–6PubMedGoogle Scholar
  224. 224.
    McLean AJ, Morgan DJ. Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet 1991; 21: 42–69PubMedCrossRefGoogle Scholar
  225. 225.
    Morgan DJ, Smallwood RA. Clinical significance of pharmacokinetic models of hepatic elimination. Clin Pharmacokinet 1990; 18: 61–76PubMedCrossRefGoogle Scholar
  226. 226.
    Reichen J, Le M. Verapamil favorably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver. J Clin Invest 1986; 78: 448–55PubMedCrossRefGoogle Scholar
  227. 227.
    Leier CV. Regional blood flow responses to vasodilatators and inotropes in congestive heart failure. Am J Cardiol 1988; 62: 86E–93EPubMedCrossRefGoogle Scholar
  228. 228.
    Wynne HA, Goudevenos J, Rawlings MD, et al. Hepatic drug clearance: The effect of age using indocyanine green as a model compound. Br J Clin Pharmacol 1990; 30: 634–7PubMedCrossRefGoogle Scholar
  229. 229.
    Bauer L, Horn JR, Opheim KE. Variability of indocyanine green pharmacokinetics in healthy adults. Clin Pharmacol 1987; 8: 54–5Google Scholar
  230. 230.
    Skak C, Keiding S. Methodical problems in the use of indocyanine green to estimate hepatic blood flow and ICG clearance in man. Liver 1987; 7: 155–62PubMedCrossRefGoogle Scholar
  231. 231.
    Keiding S. Galactose clearance measurements and liver blood flow. Gastroenterology 1988; 94: 477–81PubMedGoogle Scholar
  232. 232.
    Huet PM, Villeneuve JP. Determinants of drug disposition in patients with cirrhosis. Hepatology 1983; 3: 919–8Google Scholar
  233. 233.
    Kawasaki S, Sugiyama Y, Iga T, et al. Hepatic clearances of antipyrine, indocyanine green, and galactose in normal subjects and in patients with chronic liver diseases. Clin Pharmacol Ther 1988; 44: 217–42PubMedCrossRefGoogle Scholar
  234. 234.
    Clements D, West R, Elias E. Comparison of bolus and infusion methods for estimating hepatic blood flow in patients with liver disease using indocyanine green. J Hepatol 1987; 5: 282–7PubMedCrossRefGoogle Scholar
  235. 235.
    Wang P, Chandry IH. Hepatic extraction of indocyanine green is depressed early in sepsis despite increased hepatic blood flow and cardiac output. Arch Surg 1991; 126: 219–24PubMedCrossRefGoogle Scholar
  236. 236.
    Vaubourdolle M, Gufflet V, Chazouillères O, et al. Indocyanine green-sulfobromophthalein pharmacokinetics for diagnosing primary biliary cirrhosis and assessing histological severity. Clin Chem 1991; 37: 1688–90PubMedGoogle Scholar
  237. 237.
    Housten JB. Drug metabolite kinetics. Pharmacol Ther 1982; 15: 521–52CrossRefGoogle Scholar
  238. 238.
    Weiss M. A general model of metabolite kinetics following intravenous and oral administration of the parent drug. Biopharm Drug Dispos 1988; 9: 159–76PubMedCrossRefGoogle Scholar
  239. 239.
    Watkins PB, Wrighton SA, Schuetz EG, et al. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest 1987; 80: 1029–36PubMedCrossRefGoogle Scholar
  240. 240.
    Kolars JC, Schmiedlin-Ren P, Schuetz JD, et al. Identification of rifampicin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 1992; 90: 1871–8PubMedCrossRefGoogle Scholar
  241. 241.
    Kolars JC, Awni WM, Merion RM, et al. First-pass metabolism of cyclosporin by the gut. Lancet 1991; 338: 1488–90PubMedCrossRefGoogle Scholar
  242. 242.
    Brockmöller J, Neumayer H-H, Wagner K, et al. Pharmacokinetic interaction between cyclosporin and diltiazem. Eur J Clin Pharmacol 1990; 38: 237–42PubMedCrossRefGoogle Scholar
  243. 243.
    Jackson PR, Tucker GT, Lennard MS, et al. Polymorphic drug oxidation: pharmacokinetic basis and comparison of experimental indices. Br J Clin Pharmacol 1986; 22: 541–50PubMedCrossRefGoogle Scholar
  244. 244.
    Eichelbaum M, Gross AS. The genetic polymorphism of debrisoquine/sparteine metabolism — clinical aspects. In: Kalow W, editor. Pharmacogenetics of Drug Metabolism. New York: Pergamon Press, 1992: 625–48Google Scholar
  245. 245.
    Lennard MS. Genetic polymorphism of spartein/debrisoquine oxidation: a reappraisal. Pharmacol Toxicol 1990; 67: 273–83PubMedCrossRefGoogle Scholar
  246. 246.
    Brøsen K, Gram LF. Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol 1989; 36: 537–47PubMedCrossRefGoogle Scholar
  247. 247.
    Gonzalez FJ, Skoda RC, Kimura S, et al. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 1988; 331: 442–6PubMedCrossRefGoogle Scholar
  248. 248.
    Kimura S, Umeno M, Skoda RC, et al. The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet 1989; 45: 889–904PubMedGoogle Scholar
  249. 249.
    Kagimoto M, Heim M, Kagimoto K, et al. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine-study of the functional significance of individual mutations by expression of chimeric genes. J Biol Chem 1990; 265: 17209–14PubMedGoogle Scholar
  250. 250.
    Skoda RC, Gonzalez FJ, Demierre A, et al. Two mutant alleles of the human cytochrome P-450db1 gene (P450C2D1) associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci USA 1988; 85: 5240–3PubMedCrossRefGoogle Scholar
  251. 251.
    Heim M, Meyer UA. Genetic polymorphism of debrisoquine oxidation: restriction fragment analysis and allele-specific amplification of mutant alleles of CYP2D6. Methods Enzymol 1991; 206: 173–83PubMedCrossRefGoogle Scholar
  252. 252.
    Heim MH. Polymerase chain reaction and its potential as a pharmacokinetic tool. Clin Pharmacokinet 1992; 23: 321–7PubMedCrossRefGoogle Scholar
  253. 253.
    Gough AC, Miles JS, Spurr NK, et al. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 1990; 347: 773–5PubMedCrossRefGoogle Scholar
  254. 254.
    Armstrong M, Fairbrother K, Idle JR, et al. The cyctochrome P450 CYP2D6 allelic variant CYP2D6J and related polymorphisms in a European population. Pharmacogenetics 1994; 4: 73–81PubMedCrossRefGoogle Scholar
  255. 255.
    Wang S-L, Huang J-D, Lai M-D, et al. Molecular basis of genetic variation in debrisoquine hydroxylation in Chinese subjects: polymorphism in RFLP and DNA sequence of CYP2D6. Clin Pharmacol Ther 1993; 53: 410–8PubMedCrossRefGoogle Scholar
  256. 256.
    Tyndale R, Aoyama T, Broly F, et al. Identificaton of a new variant CYP2D6 allele lacking the codon encoding Lys-281: possible association with the poor metabolizer phenotype. Pharmacogenetics 1991; 1: 26–32PubMedCrossRefGoogle Scholar
  257. 257.
    Roots I, Brockmöller J, Drakoulis N et al. Mutant genes of cytochrome P-450IID6, glutathione S-transferase class Mu, and arylamine N-acetyltransferase in lung cancer patients. Clin Invest 1992; 70: 307–19CrossRefGoogle Scholar
  258. 258.
    Johansson I, Lundqvist E, Bertilsson L, et al. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 1993; 90: 11825–9PubMedCrossRefGoogle Scholar
  259. 259.
    Staffeidt B, Brockmöller J, Kerb R, et al. Evaluation of the CYP2D6 genotyping in healthy volunteers and hospital patients. J Basic Clin Physiol Pharmacol 1992; 3 Suppl: 249Google Scholar
  260. 260.
    Graf T, Broly F, Hoffmann F, et al. Prediction of phenotype for acetylation and for debrisoquine hydroxylation by DNA-tests in healthy human volunteers. Eur J Clin Pharmacol 1992; 43: 399–403PubMedCrossRefGoogle Scholar
  261. 261.
    Dahl ML, Johansson I, Palmertz MP, et al. Analysis of the CYP2D6 gene in relation to debrisoquin and desipramine hydroxylation in a Swedish population. Clin Pharmacol Ther 1992; 51: 12–7PubMedCrossRefGoogle Scholar
  262. 262.
    Broly D, Gaedigk A, Heim M, et al. Debrisoquine/sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population. DNA Cell Biol 1991; 8: 545–58CrossRefGoogle Scholar
  263. 263.
    Daly AK, Armstrong M, Monkman SC, et al. Genetic and metabolic criteria for the assignment of debrisoquine 4-hydroxylation (cytochrome P4502D6) phenotypes. Pharmacogenetics 1991; 1: 33–41PubMedCrossRefGoogle Scholar
  264. 264.
    Roots I, Drakoulis N, Brockmöller J. Polymorphic enzymes and cancer risk: concepts, methodology and data review. In: Kalow W, editor. Pharmacogenetics of Drug Metabolism. New York: Pergamon Press, 1992: 815–41Google Scholar
  265. 265.
    Romkes M, Faletto MB, Blaisdell JA, et al. Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450 IIC subfamily. Biochemistry 1991; 30: 3247–55PubMedCrossRefGoogle Scholar
  266. 266.
    Alván G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990; 39: 533–7PubMedCrossRefGoogle Scholar
  267. 267.
    Wilkinson GR, Guengerich FP, Branch RA. Genetic polymorphism of S-mephenytoin hydroxylation. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, 1992: 657–80Google Scholar
  268. 268.
    Cederberg C, Andersson T, Skånberg I. Omeprazole: Pharmacokinetics and metabolism in man. Scand J Gastroenterol 1989; 24 Suppl. 166: 33–42CrossRefGoogle Scholar
  269. 269.
    Funck-Brentano C, Bosco O, Jacqz-Aigrain, et al. Relation between chloroguanide bioactivation to cycloguanil and the genetically determined metabolism of mephenytoin in humans. Clin Pharmacol Ther 1992; 51: 507–12PubMedCrossRefGoogle Scholar
  270. 270.
    Zhou HH, Anthony LB, Wood AJJ, et al. Induction of polymorphic 4′-hydroxylation of S-mephenytoin by rifampicin. Br J Clin Pharmacol 1990; 30: 471–5PubMedCrossRefGoogle Scholar
  271. 271.
    Hildebrand M, Seifert W, Reichenberger A. Determination of dextromethorphan metabolizer phenotype in healthy volunteers. Eur J Clin Pharmacol 1989; 36: 315–8PubMedCrossRefGoogle Scholar
  272. 272.
    Conney AH. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: GAH Glowes memorial lecture. Cancer Res 1982; 42: 4875–917PubMedGoogle Scholar
  273. 273.
    Okey AB. Enzyme induction in the cytochrome P-450 system. Pharmacol Ther 1990; 45: 241–98PubMedCrossRefGoogle Scholar
  274. 274.
    Barry M, Feely J. Enzyme induction and inhibition. Pharmacol Ther 1990; 48: 71–94PubMedCrossRefGoogle Scholar
  275. 275.
    Park BK, Kitteringham NR. Assessment of enzyme induction and enzyme inhibition in humans: Toxicological implications. Xenobiotica 1990; 20: 1171–85PubMedCrossRefGoogle Scholar
  276. 276.
    Bock KW, Lipp HP, Bock-Hennig BS. Induction of drug-metabolizing enzymes by xenobiotics. Xenobiotica 1990; 20: 1101–11PubMedCrossRefGoogle Scholar
  277. 277.
    Schuetz EG, Wrighton SA, Barwick JL, et al. Induction of cytochrome P-450 by glucocorticoids in rat liver. J Biol Chem 1984; 259: 1999–2006PubMedGoogle Scholar
  278. 278.
    Burstein S, Klaiber EL. Phenobarbital-induced increase in 6β-hydroxycortisol excretion: clue to its significance in human urine. J Clin Endocrinol 1965; 25: 293–6CrossRefGoogle Scholar
  279. 279.
    Roots I, Holbe R, Hövermann W, et al. Quantitative determination by HPLC of urinary 6β-hydroxycortisol, an indicator of enzyme induction by rifampicin and antiepileptic drugs. Eur J Clin Pharmacol 1979; 16: 63–71PubMedCrossRefGoogle Scholar
  280. 280.
    Ohnhaus EE, Park BK. Measurement of urinary 6-β-hydroxycortisol excretion as an in vivo parameter in the clinical assessment of the microsomal enzyme-inducing capacity of antipyrine, phenobarbitone and rifampicin. Eur J Clin Pharmacol 1979; 15: 139–45PubMedCrossRefGoogle Scholar
  281. 281.
    Park BK. Assessment of urinary 6β-hydroxycortisol as an in vivo index of mixed-function oxygenase activity. Br J Clin Pharmacol 1981; 12: 97–102PubMedGoogle Scholar
  282. 282.
    Ohnhaus EE, Breckenridge AM, Park BK. Urinary excretion of 6β-hydroxycortisol and the time course measurement of enzyme induction in man. Eur J Clin Pharmacol 1989; 36: 39–46PubMedCrossRefGoogle Scholar
  283. 283.
    Ged C, Rouillon JM, Pichard L, et al. The increase in urinary excretion of 6β-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. Br J Clin Pharmacol 1989; 28: 373–87PubMedCrossRefGoogle Scholar
  284. 284.
    Bienvenu T, Rey E, Pons G, et al. A simple non-invasive procedure for the investigation of cytochrome P-450 IIIA dependent enzymes in humans. Int J Clin Pharmacol Ther Toxicol 1991; 29: 441–5PubMedGoogle Scholar
  285. 285.
    Aarts EM. Evidence for the function of D-glucaric acid as an indicator for drug induced enhanced metabolism through the glucuronic acid pathway in man. Biochem Pharmacol 1966; 15: 1469–77PubMedCrossRefGoogle Scholar
  286. 286.
    Hunter J, Carrella M, Maxwell JD, et al. Urinary D-glucaric acid excretion as a test for hepatic enzyme induction in man. The Lancet 1971; 572–4Google Scholar
  287. 287.
    Heinemeyer G, Roots I, Lestau P, et al. D-glucaric acid excretion in critical care patients — comparison with 6β-hydroxycortisol excretion and serum γ-glutamyltranspeptidase activity and relation to multiple drug therapy. Br J Clin Pharmacol 1986; 21: 9–18PubMedCrossRefGoogle Scholar
  288. 288.
    Rosalki SB, Rau D. Serum gamma-glutamyl transpeptidase activity in alcoholism. Clin Chim Acta 1972; 39: 41–7PubMedCrossRefGoogle Scholar
  289. 289.
    Okesiona AB, Donaldson D, Lascelles PT. Serum gamma glutamyl transferase activities in epileptic patients receiving carbamazepine monotherapy. Ann Clin Biochem 1991; 28: 307–8Google Scholar
  290. 290.
    Hildebrandt AG, Roots I, Speck M, et al. Evaluation of in vivo parameters of drug metabolising enzyme activity in man after administration of clemastine, phenobarbital or placebo. Eur J Clin Pharmacol 1975; 8: 327–36PubMedCrossRefGoogle Scholar
  291. 291.
    Omiecinski CJ, Redlich CA, Costa P. Induction and developmental expression of cytochrome P450IA1 messenger RNA in rat and human tissues: detection by polymerase chain reaction. Cancer Res 1990; 50: 4315–21PubMedGoogle Scholar
  292. 292.
    Heuvel JPV, Clark GC, Thompson CL, et al. CYP1A1 mRNA levels as a human exposure biomarker: use of quantitative polymerase chain reaction to measure CYP1A1 expression in human peripheral blood lymphocytes. Carcinogenesis 1993; 14: 2003–6CrossRefGoogle Scholar
  293. 293.
    Sauer RT, editor. Protein-DNA interactions. Methods Enzymol 1991; 208: 1–700Google Scholar
  294. 294.
    Kawajiri K, Nakachi K, Imai K, et al. Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P450 1A1 gene. FEBS Lett 1990; 263: 131–3PubMedCrossRefGoogle Scholar
  295. 295.
    Petersen DD, McKinney CE, Ikeya K, et al. Human CYP1A1 gene: cosegregation of the enzyme inducibility phenotype and an RFLP. Am J Hum Genet 1991; 48: 720–5PubMedGoogle Scholar
  296. 296.
    Drakoulis N, Cascorbi I, Brockmöller J, et al. Polymorphisms in the human CYP1A1 gene as susceptibility factors for lung cancer: exon-7 mutation (4889 A to G), and a T to C mutation in the 3′-flanking region. Clin Invest 1994; 72: 240–8CrossRefGoogle Scholar
  297. 297.
    Hayashi SI, Watanabe J, Kawajiri K. Genetic polymorphisms in the 5’-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene. J Biochem 1991; 110: 559–65PubMedGoogle Scholar
  298. 298.
    Khan IU, Bickers DR, Haqqi TM, et al. Induction of CYP1A1 mRNA in rat epidermis and cultured human epithelial keratinocytes by benz(a)anthracene and β-naphthoflavone. Drug Metab Dispos 1992; 20: 620–4PubMedGoogle Scholar
  299. 299.
    Waxman DJ, Sundseth SS, Srivastava PK, et al. Gene-specific oligonucleotide probes for α, µ, π and microsomal rat glutathione S-transferases: analysis of liver transferase expression and its modulation by hepatic enzyme inducers and platinium anticancer drugs. Cancer Res 1992; 52: 5797–802PubMedGoogle Scholar
  300. 300.
    Diaz D, Fabre I, Davjat M, et al. Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. Gastroenterology 1990; 99: 737–47PubMedGoogle Scholar
  301. 301.
    McDonnell WM, Scheimann JM, Traber PG. Induction of cytochrome P450IA genes (CYP1A) by omeprazole in the human alimentary tract. Gastroenterology 1992; 103: 1509–16PubMedGoogle Scholar
  302. 302.
    Andersson T, Bergstrand R, Cederberg C, et al. Omeprazole treatment does not affect the metabolism of caffeine. Gastroenterology 1991; 101: 943–7PubMedGoogle Scholar
  303. 303.
    Whitlock JP. The regulation of gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Pharmacol Rev 1987; 39: 147–61PubMedGoogle Scholar
  304. 304.
    Nebert DW, Jones JJ. Regulation of the mammalian cytochrome P4501(CYP1A1) gene. Int J Biochem 1989; 21: 243–252PubMedCrossRefGoogle Scholar
  305. 305.
    Puga A, Raychaudhuri B, Nebert DW. Transscriptional derepression of the murine Cypla-1 gene by mevinolin. FASEB J 1992; 6: 777–85PubMedGoogle Scholar
  306. 306.
    Daujat M, Peryt B, Lesca P, et al. Omeprazole, an inducer of human CYP1A1 and 1A2, is not a ligand for the Ah receptor. Biochem Biophys Res Commun 1992; 188: 820–5PubMedCrossRefGoogle Scholar
  307. 307.
    Quattrochi LC, Tukey RH. Nuclear uptake of the Ah (dioxin) receptor in response to omeprazole: transcriptional activation of the human CYP1 A1 gene. Mol Pharmacol 1993; 43: 504–8PubMedGoogle Scholar
  308. 308.
    Andus R, Bauer J, Gerok W. Effects of cytokines on the liver. Hepatology 1991; 13: 364–75PubMedCrossRefGoogle Scholar
  309. 309.
    Israel BC, Blouin RA, McIntyre W, et al. Effects of interferon-α monotherapy on hepatic drug metabolism in cancer patients. Br J Clin Pharmacol 1993; 36: 229–35PubMedCrossRefGoogle Scholar
  310. 310.
    Murray M, Zaluzny L, Farrell GC. Drug metabolism in cirrhosis-selective changes in cytochrome P-450 isoenzymes in the choline-deficient rat model. Biochem Pharmacol 1986; 35: 1817–24PubMedCrossRefGoogle Scholar
  311. 311.
    Bienvenu T, Pons G, Rey E, et al. Effect of growth hormone on caffeine metabolism in hypophysectomized rats. Drug Metab Dispos 1990; 18: 327–30PubMedGoogle Scholar
  312. 312.
    Morgan ET. Down-regulation of multiple cytochrome P450 gene products by inflammatory mediators in vivo — independence from the hypothalamo-pituitary axis. Biochem Pharmacol 1993; 45: 415–9PubMedCrossRefGoogle Scholar
  313. 313.
    Abdel-Razzaz Z, Loyer P, Fantrel A, et al. Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. Mol Pharmacol 1993; 44: 707–15Google Scholar
  314. 314.
    Bass NM, Williams RL. Guide to drug dosage in hepatic disease. Clin Pharmacokinet 1988; 15: 396–420PubMedCrossRefGoogle Scholar
  315. 315.
    Williams RJ. Drug administration in hepatic disease. N Engl J Med 1983; 309: 1616–22PubMedCrossRefGoogle Scholar
  316. 316.
    Naranjo CA, Busto U, Janecek E, et al. An intensive drug monitoring study suggesting possible clinical irrelevance of impaired drug disposition in liver disease. Br J Clin Pharmacol 1983; 15: 451–8PubMedCrossRefGoogle Scholar
  317. 317.
    Svensson CK, Woodruff MN, Baxter JG, et al. Free drug concentration monitoring in clinical practice. Rationale and current status. Clin Pharmacokinet 1986; 11: 450–69PubMedCrossRefGoogle Scholar
  318. 318.
    Barry M, Keeling PWN, Weir D, et al. Severity of cirrhosis and the relationship of α1-acid glycoprotein concentration to plasma protein binding of lidocaine. Clin Pharmacol Ther 1990; 47: 366–70PubMedCrossRefGoogle Scholar
  319. 319.
    Herve F, Gomas E, Duche JC, et al. Evidence for differences in the binding of drugs to the two main genetic variants of human α1-acid glycoprotein. Br J Clin Pharmacol 1993; 36: 241–9PubMedCrossRefGoogle Scholar
  320. 320.
    Tillement JP, Lindenlaub E. Protein binding and drug transport. Stuttgart: Schattauer Verlag, 1986Google Scholar
  321. 321.
    Westphal J-F, Brogard J-M. Clinical pharmacokinetics of newer antibacterial agents in liver disease. Clin Pharmacokinet 1993; 24: 46–58PubMedCrossRefGoogle Scholar
  322. 322.
    Bakti G, Fisch HU, Karlaganis G, et al. Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: Model experiments with triazolam. Hepatology 1987; 7: 629–38PubMedCrossRefGoogle Scholar
  323. 323.
    Zimmermann HJ. Update of hepatotoxicity due to classes of drugs in common clinical use: non-steroidal drugs, anti-inflammatory drugs, antibiotics, antihypertensives, and cardiac and psychotropic agents. Semin Liver Dis 1990; 10: 322–38CrossRefGoogle Scholar
  324. 324.
    Murray JM, Rowlands BJ, Trinick TR. Indocyanine green clearance and hepatic function during prolonged anaesthesia: Comparison of halothane with isoflurane. Br J Anaesth 1992; 68: 168–71PubMedCrossRefGoogle Scholar
  325. 325.
    Beckett GJ, Foster GR, Hussey AJ, et al. Plasma glutathione S-transferase and F protein are more sensitive than alanine aminotransferase as markers of paracetamol (acetaminophen)-induced liver damage. Clin Chem 1989; 35: 2186–9PubMedGoogle Scholar
  326. 326.
    Evans EW, Schentag JJ, Jusko WJ. Applied pharmacokinetics. Principles of therapeutic drug monitoring. San Francisco: Applied Therapeutics, 1980; 1–708Google Scholar
  327. 327.
    Köppel C, Brockmöller J, Roots I. Genotyping of hereditary defective drug metabolism as an aid in serious drug overdosage. In: Kaempe B, editor. Forensic toxicology: proceedings of the 29th international meeting. Copenhagen: Mackeenzie, 1991: 505–14Google Scholar
  328. 328.
    Ross MP, Allen-Webb EM, Pappas JB, et al. Amrinone associated thrombocytopenia: pharmacokinetic analysis. Clin Pharmacol Ther 1993; 53: 661–7PubMedCrossRefGoogle Scholar
  329. 329.
    Eichelbaum M, Gross AS. The genetic polymorphism of debrisoquine/sparteine metabolism — clinical aspects. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, 1992: 625–48Google Scholar
  330. 330.
    Woosley RL. Antiarrhythmic drugs. Annu Rev Pharmacol Toxicol 1991; 31: 427–55PubMedCrossRefGoogle Scholar
  331. 331.
    Cardiac Arrythmia Suppression Trial (CAST Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321: 406–12CrossRefGoogle Scholar
  332. 332.
    Balant-Gorgia AE, Balant LP, Andreoli A. Pharmacokinetic optimisation of the treatment of psychosis. Clin Pharmacokinet 1993; 25: 217–36PubMedCrossRefGoogle Scholar
  333. 333.
    Koymans L, Donné-op den Kelder GM, Koppele TEJM, et al. Cytochromes P450: Their active site structure and mechanism of oxidation. Drug Metab Rev 1993; 25: 325–87PubMedCrossRefGoogle Scholar
  334. 334.
    Sjöqvist F. Pharmacogenetic factors in the metabolism of tricyclic antidepressants and some neuroleptics. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, 1992: 689–700Google Scholar
  335. 335.
    Dahl M-L, Bertilsson L. Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenetics 1993; 3: 61–70PubMedCrossRefGoogle Scholar
  336. 336.
    Brøsen K. Recent developments in hepatic drug oxidation — implications for clinical pharmacokinetics. Clin Pharmacokinet 1990; 18: 220–39PubMedCrossRefGoogle Scholar
  337. 337.
    Spina E, Ancione M, DiRosa AE, et al. Polymorphic debrisoquine oxidation and acute neuroleptic-induced adverse effects. Eur J Clin Pharmacol 1992; 42: 347–8PubMedCrossRefGoogle Scholar
  338. 338.
    Müller N, Brockmöller J, Roots I. Extremely long plasma half-life of amitriptyline in a women with the cytochrome P450IID6 29/29-kilobase wild-type allele — a slowly reversible interaction with fluoxetine. Ther Drug Monit 1991; 13: 533–6PubMedCrossRefGoogle Scholar
  339. 339.
    Bluhm RE, Wilkinson GR, Shelton R, et al. Genetically determined drug-metabilizing activity and desipramine-associated cardiotoxicity: a case report. Clin Pharmacol Ther 1993; 53: 89–95PubMedCrossRefGoogle Scholar
  340. 340.
    Evans WE. Alternative approaches for phase I studies of anticancer drugs: A role for therapeutic drug monitoring. Ther Drug Monit 1993; 15: 492–7PubMedCrossRefGoogle Scholar
  341. 341.
    Boddy AV, Furtun Y, Sardas S, et al. Interindividual variation in the activation and inactivation metabolic pathways of cyclophosphamide. J Natl Cancer Inst 1992; 84: 1744–8PubMedCrossRefGoogle Scholar
  342. 342.
    Yoshida A. Molecular genetics of human aldehyde dehydrogenase. Pharmacogenetics 1992; 2: 139–47PubMedCrossRefGoogle Scholar
  343. 343.
    Harris BE, Carpenter JT, Diasio RB. Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome. Cancer 1991; 68: 499–501PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Jürgen Brockmöller
    • 1
  • Roots Ivar
    • 1
  1. 1.Institut für Klinische PharmakologieUniversitätsklinikum Charité, Humboldt-Universität BerlinBerlinGermany

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