Clinical Pharmacokinetics

, Volume 7, Issue 5, pp 373–400 | Cite as

Ethnic Differences in Drug Metabolism

  • W. Kalow


Interethnic differences in drug-metabolising capacity may be substantial, and they are sufficiently frequent to warrant attention. Such differences may consist of different mean values of quantitative traits in separate populations, or of different frequency distributions as produced by the occurrence of genetic enzyme variants.

The collection of population data requires the investigation of substantial numbers of subjects. This may be no problem if drug-metabolising enzymes occur in blood or are sufficiently stable in their tissues to allow investigation in vitro. However, if investigations require the use of probe drugs, new efforts are needed to adapt pharmacokinetic methods to make them suitable for population studies. This development of methods is further called for because genetic variants seem to be more easily detected through the assessment of particular metabolites than through the determination of pharmacokinetic parameters of the parent drug.

Many studies with probe drugs comparing different populations have given results that are equivocal in terms of the nature-nurture interplay. However, a set of data with antipyrine has pointed to environmental factors as the principal determinant of differences in metabolising capacity, while data with debrisoquine have indicated monogenically controlled variation of one facet of the cytochrome P-450 system. In several instances, statistically significant differences between population means have been established by testing small numbers of subjects, numbers insufficient to establish distribution patterns that would allow the recognition of genetic polymorphism.

The populations studied range from Greenlanders to South African Blacks, but most comparisons pertain to Caucasians and Orientals.


Clinical Pharmacology Drug Metabolism Ethnic Difference Antipyrine Debrisoquine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ahmad, S.: The functional roles of cytochrome P-450 mediated systems: Present knowledge and future areas of investigation. Drug Metabolism Reviews 10: 1–14 (1979).PubMedCrossRefGoogle Scholar
  2. Alexanderson, B.: Prediction of steady-state plasma levels of nortriptyline from single oral dose kinetics: A study in twins. European Journal of Clinical Pharmacology 6: 44–53 (1973).PubMedCrossRefGoogle Scholar
  3. Alvan, G.: Individual differences in the disposition of drugs metabolised in the body. Clinical Pharmacokinetics 3: 155–175 (1978).PubMedCrossRefGoogle Scholar
  4. Alvares, A.P.; Kappas, A.; Eiseman, J.L.; Anderson, K.E.; Pantuck, C.B.; Pantuck, E.J.; Hsiao, K.-C.; Garland, W.A. and Conney, A.H.: Intraindividual variation in drug disposition. Clinical Pharmacology and Therapeutics 26: 407–419 (1979a).PubMedGoogle Scholar
  5. Alvares, A.P.; Pantuck, E.J.; Anderson, K.E.; Kappas, A. and Conney, A.H.: Regulation of drug metabolism in man by environmental factors. Drug Metabolism Reviews 9: 185–205 (1979b).PubMedCrossRefGoogle Scholar
  6. Andoh, B.; Idle, J.R.; Sloan, T.P.; Smith, R.L. and Woolhouse, N.: Inter-ethnic and inter-phenotype differences, among Ghanaians and Caucasians in the metabolic hydroxylation of Phenytoin. British Journal of Clinical Pharmacology 9: 282P–283P (1980).CrossRefGoogle Scholar
  7. Andreasen, P.B.; Frøland, A.; Skovsted, L.; Andersen, S.A. and Hauge, M.: Diphenylhydantoin half-life in man and its inhibition by Phenylbutazone: The role of genetic factors. Acta Medica Scandinavica 193: 561–564 (1973).PubMedCrossRefGoogle Scholar
  8. Arnold, K. and Gerber, N.: The rate of decline of diphenylhydantoin in human plasma. Clinical Pharmacology and Therapeutics 11: 121–134 (1969).Google Scholar
  9. Balasubramaniam, K.; Lucas, S.B.; Mawer, G.E. and Simons, P.J.: The kinetics of amylobarbitone metabolism in healthy men and women. British Journal of Pharmacology 39: 564–572 (1970).PubMedCrossRefGoogle Scholar
  10. Baty, J.D.; Price Evans, D.A. and Robinson, P.A.: The identification of 6-methoxy 8-aminoquinoline as a metabolite of Primaquine in man. Biomedical Mass Spectrometry 2: 304–306 (1975).CrossRefGoogle Scholar
  11. Bennion, L.J. and Li, T.-K.: Alcohol metabolism in American Indians and Whites. Lack of racial differences in metabolic rate and liver alcohol dehydrogenase. New England Journal of Medicine. 294: 9–13 (1976).PubMedCrossRefGoogle Scholar
  12. Bernstein, R.E.. Isoniazid hepatotoxicity and acetylation during tuberculosis chemoprophylaxis. American Review of Respiratory Disease 121: 429–430 (1980).Google Scholar
  13. Berry, R.J. and Peters, J.: Heterogeneous heterozygosities in Mus musculus populations. Proceedings of the Royal Society of London; B 197: 485–503 (1977).CrossRefGoogle Scholar
  14. Bertilsson, L.; Dengler, H.J.; Eichelbaum, M. and Schulz, H.-U.: Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine. European Journal of Clinical Pharmacology 17: 153–155 (1980a).PubMedCrossRefGoogle Scholar
  15. Bertilsson, L.; Eichelbaum, M.; Mellström, B.; Säwe, J.; Schulz, H.-U. and Sjöqvist, F.: Nortriptyline and antipyrine clearance in relation to debrisoquine hydroxylation in man. Life Sciences 27: 1673–1677 (1980b).PubMedCrossRefGoogle Scholar
  16. Branch, R.A.; Salih, S.Y. and Homeida, M.: Racial differences in drug metabolizing ability: A study with antipyrine in the Sudan. Clinical Pharmacology and Therapeutics 24: 283–286 (1978).PubMedGoogle Scholar
  17. Branch, RA. and Shand, D.G.: A re-evaluation of intersubject variation in enzyme induction in man. Clinical Pharmacokinetics 4: 104–110 (1979).PubMedCrossRefGoogle Scholar
  18. Breimer, D.D.: Clinical pharmacokinetics of hypnotics. Clinical Pharmacokinetics 2: 93–109 (1977).PubMedCrossRefGoogle Scholar
  19. Breimer, D.D.: Personal communication (1981).Google Scholar
  20. Brown, S.S.; Kalow, W.; Pilz, W.; Whittaker, M. and Woronick, C.L.: The plasma cholinesterases: A new perspective. (For the Commission on Toxicology, IUPAC Section on Clinical Chemistry.) Advances in Clinical Chemistry 22: 1–123 (1981).Google Scholar
  21. Buchanan, N.; Bill, P.; Moodley, G. and Eyberg, C.: The metabolism of phenobarbitone, Phenytoin and antipyrine in black patients. South African Medical Journal 52: 394–395 (1977).PubMedGoogle Scholar
  22. Carro-Ciampi, G.; Kadar, D. and Kalow, W.: Distribution of serum paraoxon-hydrolyzing activities in a Canadian population. Canadian Journal of Physiology and Pharmacology 59: 904–907 (1981).PubMedCrossRefGoogle Scholar
  23. Chang, T.; Okerholm, R.A. and Glazko, A.J.: Identification of diphenhydramine (Benadryl®) metabolites in human subjects. Research Communications in Chemical Pathology and Pharmacology 9: 391–404 (1974).PubMedGoogle Scholar
  24. Chapron, D.J.; Kramer, P.A. and Mercik, S.A.: Kinetic discrimination of three sulfamethazine acetylation phenotypes. Clinical Pharmacology and Therapeutics 27: 104–113 (1980).PubMedCrossRefGoogle Scholar
  25. Chiba, K.; Ishizaki, T.; Miura, H. and Minagawa, K.: Michaelis-Menten pharmacokinetics of diphenylhydantoin and application in the pediatric age patient. Journal of Pediatrics 96: 479–484 (1980).PubMedCrossRefGoogle Scholar
  26. Clarke, B.C.: The evolution of genetic diversity. Proceedings of the Royal Society of London; B 205: 453–474 (1979).CrossRefGoogle Scholar
  27. Cooksley, W.G.E.; Farrell, G.C.; Cash, G.A. and Powell, L.W.: The interaction of cigarette smoking and chronic drug ingestion on human drug metabolism. Clinical and Experimental Pharmacology and Physiology 6: 527–533 (1979).PubMedCrossRefGoogle Scholar
  28. Dam, M.; Larsen, L. and Christiansen, J.: Phenytoin: Ethnic differences in plasma level and clearance-, in Gardner-Thorpe et al. (Eds) Antiepileptic Drug Monitoring, pp. 73–80 (Pittman Medical Publishing, England 1977).Google Scholar
  29. Danhof, M. and Breimer, D.D.: Therapeutic drug monitoring in saliva. Clinical Pharmacokinetics 3: 39–57 (1978).PubMedCrossRefGoogle Scholar
  30. Danhof, M.; de Groot-van der Vis, E. and Breimer, D.D.: Assay of antipyrine and its primary metabolites in plasma, saliva and urine by high-performance liquid chromatography and some preliminary results in man. Pharmacology 18: 210–223 (1979).PubMedCrossRefGoogle Scholar
  31. Davies, D.S.; Kahn, G.C.; Murray, S.; Brodie, M.J. and Boobis, A.R.: Evidence for an enzymatic defect in the 4-hydroxylation of debrisoquine by human liver. British Journal of Clinical Pharmacology 11: 89–91 (1981).PubMedCrossRefGoogle Scholar
  32. Desai, N.K.; Sheth, U.K.; Mucklow, J.C.; Fraser, H.S.; Bulpitt, C.J.; Jones, S.W. and Dollery, C.T.: Antipyrine clearance in Indian villagers. British Journal of Clinical Pharmacology 9: 387–394 (1980).PubMedCrossRefGoogle Scholar
  33. Dollery, C.T.; Fraser, H.S.; Mucklow, J.C. and Bulpitt, C.K.: Contribution of environmental factors to variability in human drug metabolism. Drug Metabolism Reviews 9: 207–220 (1979).PubMedCrossRefGoogle Scholar
  34. Don, M.M.; Masters, C.J. and Winzor, D.J.: Further evidence for the concept of bovine plasma arylesterase as a lipoprotein. Biochemical Journal 151: 625–630 (1975).PubMedGoogle Scholar
  35. Dormandy, T.L.: Free-radical oxidation and antioxidants. Lancet 1: 647–650 (1978).PubMedCrossRefGoogle Scholar
  36. du Souich, P.; McLean, A.J.; Stoeckel, K.; Ohlendorf, D. and Gibaldi, M.: Screening methods using sulfamethazine for determining acetylator phenotype. Clinical Pharmacology and Therapeutics 26: 757–765 (1979).PubMedGoogle Scholar
  37. Eckerson, H.W.; Romson, J.J. and LaDu, B.M.: Differences in quantitative and qualitative enzymatic properties associated with the human serum paraoxonase polymorphism. American Journal of Human Genetics 31: A46 (1979).Google Scholar
  38. Edwards, J.A. and Price Evans, D.A.: Ethanol metabolism in subjects possessing typical and atypical liver alcohol dehydrogenase. Clinical Pharmacology and Therapeutics 8: 824–829 (1967).PubMedGoogle Scholar
  39. Eichelbaum, M.: Ein Neuentdeckter Defekt im Arzneimittelstoffwechsel des Menschen: Die Fehlende N-oxydation des Spartein. Habilitationsschrift (Bonn 1975).Google Scholar
  40. Eichelbaum, M.; Spannbrucker, N. and Dengler, H.J.: A probable genetic defect of the metabolism of sparteine; in Gorrod (Ed.) Biological Oxidation of Nitrogen, pp. 113–118 (Elsevier/North-Holland Biomedical Press, Amsterdam 1978).Google Scholar
  41. Eichelbaum, M.; Spannbrucker, N. and Dengler, H.J.: Influence of the defective metabolism of sparteine on its pharmacokinetics. European Journal of Clinical Pharmacology 16: 189–194 (1979a).PubMedCrossRefGoogle Scholar
  42. Eichelbaum, M.; Spannbrucker, N.; Steincke, B. and Dengler, H.J.: Defective N-oxidation of sparteine in man: A new pharmacogenetic defect. European Journal of Clinical Pharmacology 16: 183–187 (1979b).PubMedCrossRefGoogle Scholar
  43. Ellard, G.A.: Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis. Clinical Pharmacology and Therapeutics 19: 610–625 (1976).PubMedGoogle Scholar
  44. Ellard, G.A. and Gammon, P.T.: Pharmacokinetics of isoniazid metabolism in man. Journal of Pharmacokinetics and Biopharmaceutics 4: 83–113 (1976).PubMedGoogle Scholar
  45. Ellard, G.A. and Gammon, P.T.: Acetylator phenotyping of tuberculosis patients using matrix isoniazid or sulphadimidine and its prognostic significance for treatment with several intermittent isoniazid-containing regimens. British Journal of Clinical Pharmacology 4: 5–14 (1977).PubMedCrossRefGoogle Scholar
  46. Endrenyi, L.: Distribution characteristics of selected parameters in a population; in Bozler and van Rossum (Eds) Pharmacokinetics During Drug Development — Data Analysis and Evaluation Techniques, pp.27–28 (Fischer Verlag, Stuttgart 1981).Google Scholar
  47. Endrenyi, L.; Inaba, T. and Kalow, W.: Genetic study of amobarbital elimination based on its kinetics in twins. Clinical Pharmacology and Therapeutics 6: 701–714 (1976).Google Scholar
  48. Ewing, J.A.; Rouse, B.A.: and Pellizzari, E.D.: Alcohol sensitivity and ethnic background. American Journal of Psychiatry 131: 206–210 (1974).PubMedGoogle Scholar
  49. Farris, J.J. and Jones, B.M.: Ethanol metabolism in male American Indians and Whites. Alcoholism: Clinical and Experimental Research 2: 77–81 (1978).CrossRefGoogle Scholar
  50. Fecycz, T.D.: Metabolic disposition of Phenytoin in man (Thesis, Toronto 1980).Google Scholar
  51. Fenna, D.; Mix, L; Schaefer, O. and Gilbert, J.A.L.: Ethanol metabolism in various racial groups. Canadian Medical Association Journal 105: 472–475 (1971).PubMedGoogle Scholar
  52. Flügel, M. and Geldmacher-von Mallinckrodt, M.: Zur Kinetik des Paraoxon-spaltenden Enzyms im menschlichen Serum (EC Klinische Wochenschrift 56: 911–916 (1978).PubMedCrossRefGoogle Scholar
  53. Fraser, H.S.; Mucklow, J.C.; Bulpitt, C.J.; Khan, C.; Mould, G. and Dollery, C.T.: Environmental effects on antipyrine half-life in man. Clinical Pharmacology and Therapeutics 22: 799–808 (1977).PubMedGoogle Scholar
  54. Fraser, H.S.; Mucklow, J.C.; Bulpitt, C.J.; Kahn, C.; Mould, G. and Dollery, C.T.: Environmental factors affecting antipyrine metabolism in London factory and office workers. British Journal of Clinical Pharmacology 7: 237–243 (1979).PubMedCrossRefGoogle Scholar
  55. Fraser, H.S.; Williams, F.M.; Davies, D.L.; Draffan, G.H. and Davies, D.S.: Amylobarbitone hydroxylation kinetics in small samples of rat and human liver. Xenobiotica 6: 465–472 (1976).PubMedCrossRefGoogle Scholar
  56. Frey, W.A. and Vallee, B.L.: Digitalis metabolism and human liver alcohol dehydrogenase. Proceedings of the National Academy of Sciences, USA 77: 924–927 (1980).CrossRefGoogle Scholar
  57. Fukai, M. and Wakasugi, C.: Liver alcohol dehydrogenase in a Japanese population. Japanese Journal of Legal Medicine 26: 46–51 (1972).Google Scholar
  58. Gelboin, H.V.: Benzo[α]pyrene metabolism, activation, and carcinogenesis: Role and regulation of mixed-function oxidases and related enzymes. Physiological Reviews 60: 1107–1166 (1980).PubMedGoogle Scholar
  59. Geldmacher-von Mallinckrodt, M.; Lindorf, H.H.; Petenyi, M.; Flügel, M.; Fischer, T. and Hiller, T.: Genetisch determinierter Polymorphismus der menschlichen Serum-Paraoxonase (EC Humangenetik 17: 331–335 (1973).Google Scholar
  60. Gelehrter, T.D.: Medical progress. Enzyme induction. New Zealand Journal of Medicine 294: 522–526, 589-595, 646-651 (1976).CrossRefGoogle Scholar
  61. Gillette, J.R.: Effects of induction of cytochrome P-450 enzymes on the concentration of foreign compounds and their metabolites and on the toxicological effects of these compounds. Drug Metabolism Reviews 10: 59–87 (1979).PubMedCrossRefGoogle Scholar
  62. Goedde, H.W.; Agarwal, D.P. and Benkmann, H.-G.: Pharmacogenetics of Cholinesterase: New variants and suxamethonium sensitivity. Das Ärztliche Laboratorium 25: 219–224 (1979a).Google Scholar
  63. Goedde, H.W.; Agarwal, D.P. and Harada, S.: Alcohol metabolizing enzymes: Studies of isozymes in human biopsies and cultured fibroblasts. Clinical Genetics 16: 29–33 (1979b).PubMedCrossRefGoogle Scholar
  64. Goedde, H.W.; Harada, S. and Agarwal, D.P.: Racial differences in alcohol sensitivity: A new hypothesis. Human Genetics 51: 331–334 (1979c).PubMedCrossRefGoogle Scholar
  65. Goldberg, D.M.: The expanding role of microsomal enzyme induction, and its implications for clinical chemistry. Clinical Chemistry 26: 691–699 (1980).PubMedGoogle Scholar
  66. Greaves, J.; Evans, D.A.P.; Gillies, H.M.; Fletcher, K.A.; Bunnag, D. and Harinasuta, T.: Plasma kinetics and urinary excretion of Primaquine in man. British Journal of Clinical Pharmacology 10: 399–405 (1980).PubMedCrossRefGoogle Scholar
  67. Greenfield, N.J. and Pietruszko, R.: Two adelhyde dehydrogenases from human liver. Isolation via affinity chromatography and characterization of the isozymes. Biochimica et Biophysica Acta 483: 35–45 (1977).PubMedCrossRefGoogle Scholar
  68. Guengerich, F.P.: Isolation and purification of cytochrome P-450, and the existence of multiple forms. Pharmacology and Therapeutics 6: 99–121 (1979).PubMedCrossRefGoogle Scholar
  69. Gurtoo, H.L.; Minowada, J.; Paigen, B.; Parker, N.B. and Hayner. N.T.: Factors influencing the measurement and the reproducibility of aryl hydrocarbon hydroxylase activity in cultured human lymphocytes. Journal of the National Cancer Institute 59: 787–798 (1977).PubMedGoogle Scholar
  70. Hanna, J.M.: Metabolic responses of Chinese, Japanese and Europeans to alcohol. Alcoholism: Clinical and Experimental Research 2: 89–92 (1978).CrossRefGoogle Scholar
  71. Harada, S.; Agarwal, D.P. and Goedde, H.W.: Human liver alcohol dehydrogenase isoenzyme variations. Improved separation methods using prolonged high voltage starch-gel electrophoresis and isoelectric focusing. Human Genetics 40: 214–220 (1978a).CrossRefGoogle Scholar
  72. Harada, S.; Agarwal, D.P. and Goedde, H.W.: Isozyme variations in acetaldehyde dehydrogenase (EC. in human tissues. Human Genetics 44: 181–185 (1978b).PubMedCrossRefGoogle Scholar
  73. Harada, S.; Agarwal, D.P. and Goedde, H.W.: Electrophoretic and biochemical studies of human aldehyde dehydrogenase isozymes in various tissues. Life Sciences 26: 1773–1780 (1980a).PubMedCrossRefGoogle Scholar
  74. Harada, S.; Misawa, S.; Agarwal, D.P. and Goedde, H.W.: Liver alcohol dehydrogenase and aldehyde dehydrogenase in the Japanese: Isozyme variation and its possible role in alcohol intoxication. American Journal of Human Genetics 32: 8–15 (1980b).PubMedGoogle Scholar
  75. Harris, H.; Hopkinson, D.A. and Edwards, Y.H.: Polymorphism and the subunit structure of enzymes: A contribution to the neutralist-selectionist controversy. Proceedings of the National Academy of Sciences, USA 74: 698–701 (1977).CrossRefGoogle Scholar
  76. Hetzel, MR.; Law, M.; Keal, E.E.; Sloan, T.P.; Idle, J.R. and Smith, R.L.: Is there a genetic component in bronchial carcinoma in smokers?. Thorax 35: 709 (1980).CrossRefGoogle Scholar
  77. Hietanen, E.: Modification of hepatic drug metabolizing enzyme activities and their induction by dietary protein. General Pharmacology 11: 443–450 (1980).PubMedGoogle Scholar
  78. Idle, J.R.; Mahgoub, A.; Sloan, T.P.; Smith, R.L.; Mbanefo, C.P. and Bababunmi, E.A.: Some observations on the oxidation phenotype status of Nigerian patients presenting with cancer. Cancer Letters 11: 331–338 (1981a).PubMedCrossRefGoogle Scholar
  79. Idle, J.R.; Oates, N.S.; Shah, R.R. and Smith R.L.: Is there a genetic predisposition to phenformin-induced lactic acidosis? British Journal of Clinical Pharmacology 11: 418P–419P (1981b).Google Scholar
  80. Idle J.R.; Sloan, T.P.; Smith, R.L. and Wakile, L.A.: Application of the phenotyped panel approach to the detection of polymorphism of drug oxidation in man. British Journal of Pharmacology 66: 430P–432P (1979).Google Scholar
  81. Idle, J.R. and Smith, R.L.: Polymorphisms of oxidation at carbon centers of drugs and their clinical significance. Drug Metabolism Reviews 9: 301–317 (1979).PubMedCrossRefGoogle Scholar
  82. Illsley, N.P. and Lamartiniere, C.A.: Prenatal programming of hepatic monoamine oxidase by 5,5-diphenylhydantoin. Biochemical Pharmacology 28: 2585–2590 (1979).PubMedCrossRefGoogle Scholar
  83. Inaba, T.; Lucassen, M. and Kalow, W.: Antipyrine metabolism in the rat by three hepatic monooxygenases. Life Sciences 26: 1977–1983 (1980a).PubMedCrossRefGoogle Scholar
  84. Inaba, T.; Otton, S.V. and Kalow, W.: Deficient metabolism of debrisoquine and sparteine. Clinical Pharmacology and Therapeutics 27: 547–549 (1980b).PubMedCrossRefGoogle Scholar
  85. Inaba, T.; Stewart, D.J. and Kalow, W.: Metabolism of cocaine in man. Clinical Pharmacology and Therapeutics 23: 547–552 (1978).PubMedGoogle Scholar
  86. Inaba, T.; Tang, B.K.; Endrenyi, L. and Kalow, W.: Amobarbital — A probe of hepatic drug oxidation in man. Clinical Pharmacology and Therapeutics 20: 439–444 (1976).PubMedGoogle Scholar
  87. Inaba, T.D.; Uchino, H.; Kadar, D. and Kalow, W.: Antipyrine metabolites in two populations. Research Communications in Chemical Pathology and Pharmacology 32: 235–244 (1981).PubMedGoogle Scholar
  88. Islam, S.I.; Idle, J.R. and Smith, R.L.: The polymorphic 4-hydroxylation of debrisoquine in a Saudi arab population. Xenobiotica 10: 819–825 (1980).PubMedCrossRefGoogle Scholar
  89. Johnson, G.B.: Enzyme polymorphism and metabolism. Polymorphism among enzyme loci is related to metabolic function. Science 184: 28–37 (1974).PubMedCrossRefGoogle Scholar
  90. Kadar, D.; Tang, B.K. and Conn, A.W.: The fate of phenobarbital in near-drowning children at normal and artificially maintained low body temperature. Canadian Anaesthetists’ Society Journal (In press, 1982).Google Scholar
  91. Kalow, W.; Endrenyi, L.; Inaba, T.; Kadar, D. and Tang, B.: Pharmacogenetic investigation of amobarbital disposition. Advances in Pharmacology and Therapeutics 6: 31–40 (1978).Google Scholar
  92. Kalow, W.; Kadar, D.; Inaba, T. and Tang, B.K.: A case of deficiency of N-hydroxylation of amobarbital. Clinical Pharmacology and Therapeutics 21: 530–535 (1977).PubMedGoogle Scholar
  93. Kalow, W.; Otton, S.V.; Kadar, D.; Endrenyi, L. and Inaba, T.: Ethnic difference in drug metabolism: Debrisoquine 4-hydroxylation in Caucasians and Orientals. Canadian Journal of Physiology and Pharmacology 58: 1142–1144 (1980).PubMedCrossRefGoogle Scholar
  94. Kalow, W.; Tang, B.K.; Kadar, D.; Endrenyi, L. and Chan, F.-Y.: A method for studying drug metabolism in populations: Racial differences in amobarbital metabolism. Clinical Pharmacology and Therapeutics 26: 766–776 (1979).PubMedGoogle Scholar
  95. Kato, R.: Drug metabolism under pathological and abnormal physiological states in animals and man. Xenobiotica 7: 25–92 (1977).PubMedCrossRefGoogle Scholar
  96. Kellermann, G.H. and Luyten-Kellermann, M.: Antipyrine metabolism in man. Ufe Sciences 23: 2485–2490 (1978).Google Scholar
  97. Khanna, J.M. and Israel, Y.: Ethanol metabolism. International Review of Physiology 21: 275–315 (1980).PubMedGoogle Scholar
  98. Klein, H.; Fahrig, H. and Wolf, H.P.: Die Bestimmung der Alkoholdehydrogenase und Glutaminsäure-Oxalessigsäure-Transaminase-Aktivität der menschlichen Leber nach dem Tode. Deutsche Zeitschrift der Gesellschaft für Gerichtliche Medizin 52: 615–629 (1962).Google Scholar
  99. Kotake, A.N. and Funae, Y.: High-performance liquid chromatography technique for resolving multiple forms of hepatic membrane-bound cytochrome P-450. Proceedings of the National Academy of Sciences, USA 77: 6473–6475 (1980).CrossRefGoogle Scholar
  100. Kroos-de Haan, M.A. and Noordhoek, J.: Enhancement of antipyrine clearance and induction of antipyrine 4-hydroxylation by 3-methylcholanthrene in rats. British Journal of Pharmacology 68: 120P (1980).Google Scholar
  101. Küpfer, A.; Dick, B. and Preisig, R.: Polymorphic mephenytoin hydroxylation in man: A new phenotype in the genetic control of hepatic drug metabolism. Gastroenterology 81: 34 (1981).Google Scholar
  102. Lake, R.S.; Pezzutti, M.R.; Kropko, M.L.; Freeman, A.E. and Igel, H.J.: Measurement of benzo(a)pyrene metabolism in human monocytes. Cancer Research 37: 2530–2537 (1977).PubMedGoogle Scholar
  103. Li, T.-K.: Enzymology of human alcohol metabolism. Advances in Enzymology 45: 427–483 (1977).Google Scholar
  104. Lieber, C.S.: Metabolism of ethanol and alcoholism: Racial and acquired factors. Annals of Internal Medicine 76: 326–327 (1972).PubMedGoogle Scholar
  105. Lindgren, S.; Collste, P.; Norlander, B. and Sjöqvist, F.: Gas Chromatographic assessment of the reproducibility of Phenazone plasma half-life in young healthy volunteers. European Journal of Clinical Pharmacology 7: 381–385 (1974).PubMedCrossRefGoogle Scholar
  106. Lockridge, O.; Mottersnaw-Jackson, N.; Eckerson, H.W. and LaDu, B.N.: Hydrolysis of diacetyimorphine (heroin) by human serum Cholinesterase. Journal of Pharmacology and Experimental Therapeutics 215: 1–8 (1980).PubMedGoogle Scholar
  107. Luft, F.C.; Fineberg, N.S.; Miller, J.Z., Rankin, L.I.; Crim, C.E. and Weinberger, M.H.: The effects of age, race and heredity on glomerular filtration rate following volume expansion and contraction in normal man. American Journal of the Medical Sciences 279: 15–24 (1980).PubMedCrossRefGoogle Scholar
  108. Mahgoub, A.; Idle, J.R. and Smith, R.L.: A population and familial study of the defective alicyclic hydroxylation of debrisoquine among Egyptians. Xenobiotica 9: 51–56 (1979).PubMedCrossRefGoogle Scholar
  109. Marinovich, N.; Larsson, O. and Barber, K.: Comparative metabolism rates of ethanol in adults of aboriginal and European descent. Med. J. Australia 1 (Suppl.): 44–46 (April, 1976).Google Scholar
  110. Mbanefo, C.; Bababunmi, E.A.; Mahgoub, A.; Sloan, T.P.; Idle, J.R. and Smith, R.L.: A study of the debrisoquine hydroxylation polymorphism in a Nigerian population. Xenobiotica 10: 811–818 (1980).PubMedCrossRefGoogle Scholar
  111. Mellström, B.; Bertilsson, L.; Säwe, J.; Schulz, H.-U. and Sjöqvist, F.: E- and Z-10-hydroxylation of nortriptyline: Relationship to polymorphic debrisoquine hydroxylation. Clinical Pharmacology and Therapeutics 30: 189–193 (1981).PubMedCrossRefGoogle Scholar
  112. Mellström, B.; Bertilsson, L.; Traskman, L.; Rollins, D.; Åsberg, M. and Sjöqvist, F.: Intraindividual similarity in the metabolism of amitriptyline and chlorimipramine in depressed patients. Pharmacology 19: 282–289 (1979).PubMedCrossRefGoogle Scholar
  113. Mitchell, J.R. and Jollows, D.J.: Metabolic activation of drugs to toxic substances. Gastroenterology 68: 392–410 (1975).PubMedGoogle Scholar
  114. Mucklow, J.C.; Caraher, M.T.; Henderson, D.B.; Chapman, P.H.; Roberts, D.F. and Rawlins, M.D.: The relationship between individual dietary constituents and antipyrine metabolism in Indo-Pakistani immigrants to Britain. British Journal of Clinical Pharmacology 13: 481–486 (1982).PubMedGoogle Scholar
  115. Mucklow, J.C.; Fraser, H.S.; Bulpitt, C.J.; Kahn, C.; Mould, C. and Dollery, C.T.: Environmental factors affecting paracetamol metabolism in London factory and office workers. British Journal of Clinical Pharmacology 10: 67–74 (1980).PubMedCrossRefGoogle Scholar
  116. Nebert, D.W.: Genetic aspects of enzyme induction by drugs and chemical carcinogens; in Estabrook and Lindenlaub (Eds) The Induction of Drug Metabolism, pp. 419–452 (Schattauer Verlag, Stuttgart 1978).Google Scholar
  117. Nebert, D.W.: Genetic differences in the induction of monooxygenase activities by polycyclic aromatic compounds. Pharmacology and Therapeutics 6: 395–417 (1979a).CrossRefGoogle Scholar
  118. Nebert, D.W.: Multiple forms of inducible drug-metabolizing enzymes: A reasonable mechanism by which any organism can cope with adversity. Molecular and Cellular Biochemistry 27: 27–46 (1979b).PubMedCrossRefGoogle Scholar
  119. Nebert, D.W.: Human genetic variation in the enzymes of detoxification; in Jakoby (Ed.) Enzymatic Basis of Detoxication, pp. 25–68 (Academic Press, New York 1980).Google Scholar
  120. Nebert, D.W.: Clinical pharmacology. Possible clinical importance of genetic differences in drug metabolism. British Medical Journal 283: 537–541 (1981).PubMedCrossRefGoogle Scholar
  121. Nei, M. and Roychoudhury, A.K.: Genetic variation within and between the three major races of man, Caucasoids, Negroids and Mongoloids. American Journal of Human Genetics 26: 421–443 (1974).PubMedGoogle Scholar
  122. Nunn, M.A.K.: In vitro studies of antipyrine and amobarbital biotransformation. (Thesis, 1979).Google Scholar
  123. Omenn, G.S.: Genetic and environmental interaction in health. National Academy of Sciences/Institute of Medicine Planning Study of US Health Goals for the Year 2000, Appendix C, pp.1–20 (1981).Google Scholar
  124. Otton, S.V.; Inaba, T.; Manon, W.A. and Kalow, W.: In vitro metabolism of sparteine by human liver: Competitive inhibition by debrisoquine. Canadian Journal of Physiology and Pharmacology 60: 102–105 (1982).PubMedCrossRefGoogle Scholar
  125. Playfer, J.R.; Eze, L.C.; Bullen, M.F. and Evans, D.A.P.: Genetic polymorphism and interethnic variability of plasma paraoxonase activity. Journal of Medical Genetics 13: 337–342 (1976).PubMedCrossRefGoogle Scholar
  126. Prescott, L.F.: Kinetics and metabolism of paracetamol and phenacetin. British Journal of Clinical Pharmacology 10: 291S–298S (1980).PubMedCrossRefGoogle Scholar
  127. Price Evans, D.A.: Genetic studies involving drug metabolism in man; in Gorrod and Beckett (Eds) Drug Metabolism in Man, pp. 135–155 (Taylor and Francis, London 1978).Google Scholar
  128. Price Evans, D.A.; Mahgoub, A.; Sloan, T.P.; Idle, J.R. and Smith R.L.: A family and population study of the genetic polymorphism of debrisoquine oxidation in a White British population. Journal of Medical Genetics 17: 102–105 (1980).CrossRefGoogle Scholar
  129. Price Evans, D.A.; Manley, K.A. and McKusick, V.A.: Genetic control of isoniazid metabolism in man. British Medical Journal 2: 485–491 (1960).CrossRefGoogle Scholar
  130. Propping, P.: Pharmacogenetics. Reviews in Physiology, Biochemistry and Pharmacology 83: 124–173 (1978).Google Scholar
  131. Rainsford, K.D.; Ford, N.L.V.; Brooks, P.M. and Watson, H.M.: Plasma aspirin esterases in normal individuals, patients with alcoholic liver disease and rheumatoid arthritis; Characterization and the importance of the enzymic components. European Journal of Clinical Investigation 10: 413–420 (1980).PubMedCrossRefGoogle Scholar
  132. Rambeck, B.; Boenigk, H.E.; Dunlop, A.; Mullen, P.W.; Wadsworth, J. and Richens, A.: Predicting Phenytoin dose —a revised nomogram. Therapeutic Drug Monitoring 1: 325–333 (1979).PubMedCrossRefGoogle Scholar
  133. Rao, P.R. and Gopalam, K.B.: High incidence of the silent allele at Cholinesterase locus I in Vysyas of Andhra Pradesh (S. India). Human Genetics 52: 139–141 (1979).PubMedCrossRefGoogle Scholar
  134. Reed, T.E.: Racial comparisons of alcohol metabolism: Background, problems, and results. Alcoholism: Clinical and Experimental Research 2: 83–87 (1978).CrossRefGoogle Scholar
  135. Reed, T.E. and Kalant, H.: Bias in calculated rate of alcohol metabolism due to variation in relative amounts of adipose tissue. Journal of Studies on Alcohol 38: 1773–1776 (1977).PubMedGoogle Scholar
  136. Reed, T.E; Kalant, H.; Gibbins, R.J.; Kapur, B.M. and Rankin, J.G.: Alcohol and acetaldehyde metabolism in Caucasians, Chinese and Amerinds. Canadian Medical Association Journal 115: 851 (1976).PubMedGoogle Scholar
  137. Reilly, P.A.J.: Amobarbital biotransformation in different species (Thesis, 1978).Google Scholar
  138. Renton, K.W.; Aranda, J.V. and Eade, N.R.: NADPH- dependent lipid peroxidation and its effects on aminopyrine N-demethylation in subcellular fractions of human neonatal liver. Canadian Journal of Physiology and Pharmacology. 54: 838–843 (1976).PubMedCrossRefGoogle Scholar
  139. Richter, A.; Kadar, D.; Liszka-Hagmajer, E. and Kalow, W.; Seasonal variation of aryl hydrocarbon hydroxylase inducibility in human lymphocytes in culture. Research Communications in Chemical Pathology and Pharmacology 19: 453–475 (1978).PubMedGoogle Scholar
  140. Ritchie, J.C.; Sloan, T.P.; Idle, J.R. and Smith, R.L.: Toxicological implications of polymorphic drug metabolism; in Environmental Chemicals, Enzyme Function and Human Disease (Ciba Foundation Symposium 76), pp.219–244 (Excerpta Medica, Amsterdam 1980).Google Scholar
  141. Roe, D.A.: Interactions between drugs and nutrients. Medical Clinics of North America 63: 985–1007 (1979).PubMedGoogle Scholar
  142. Schaefer, J.M.: Alcohol metabolism and sensitivity reactions among the Reddis of South India. Alcoholism: Clinical and Experimental Research 2: 61–69 (1978).CrossRefGoogle Scholar
  143. Schaefer, J.M.: Ethnic differences in response to alcohol; in Pickens and Heston (Eds) Psychiatric Factors in Drug Abuse, pp. 219–238 (Grune and Stratum, New York 1979).Google Scholar
  144. Schull, W.J.: Genetic structure of human populations. Journal of Environmental Pathology and Toxicology 2: 1305–1312 (1979).PubMedGoogle Scholar
  145. Scott E.M. and Wright, R.C.: A third type of serum Cholinesterase deficiency in Eskimos. American Journal of Human Genetics 28: 253–256 (1976).PubMedGoogle Scholar
  146. Scheiner, L.B. and Beal S.L.: Analysis of nonexperimental pharmacokinetic data; in Albert (Ed.) Drug Absorption and Disposition: Statistical Considerations, pp. 31–49 (American Pharmaceutical Association Academy of Pharmaceutical Sciences, Washington 1980).Google Scholar
  147. Sheiner, L.B. and Beal, S.L.: Estimation of pooled pharmacokinetic parameters describing populations; in Endrenyi (Ed.) Kinetic Data Analysis, pp. 271–284 (Plenum Press, New York 1981).CrossRefGoogle Scholar
  148. Sitar, S.D. and Mannering, G.J.: Determination of apparent kinetic constants of the microsomal hydroxylation of amobarbital, hexobarbital, and pentobarbital. Drug Metabolism and Disposition 1: 663–668 (1973).PubMedGoogle Scholar
  149. Sloan, T.P.; Idle, J.R. and Smith, R.L.: Influence of DH/DL alleles regulating debrisoquine oxidation on Phenytoin hydroxylation. Clinical Pharmacology and Therapeutics 29: 493–497 (1981).PubMedCrossRefGoogle Scholar
  150. Sloan, T.P.; Mahgoub, A.; Lancaster, R.; Idle, J.R. and Smith R.L.: Polymorphism of carbon oxidation of drugs and clinical implications. British Medical Journal 2: 655–657 (1978).PubMedCrossRefGoogle Scholar
  151. Smith, M.; Hopkinson, D.A. and Harris, H.: Developmental changes and polymorphism in human alcohol dehydrogenase. Annals of Human Genetics (London) 34: 251–271 (1971).CrossRefGoogle Scholar
  152. Smith, R.L.: Some clinical and toxicological implications of polymorphic drug oxidation. Communication at Workshop ‘Polymorphism of Drug Oxidation in Man’, University of Bonn (October, 1980).Google Scholar
  153. Spector, R.; Choudhury, A.K.; Chiang, C.-K.; Goldberg, M.J. and Ghoneim, M.M: Diphenhydramine in Orientals and Caucasians. Clinical Pharmacology and Therapeutics 28: 229–234 (1980).PubMedCrossRefGoogle Scholar
  154. Srivastava, L.M.; Benkmann, H.G. and Goedde, H.W.: Review on genetic traits in Europeans, Middle East Orientals and Negroes: Serum proteins. Indian Journal of Physical Anthropology and Human Genetics 3: 85–140 (1977).Google Scholar
  155. Stamatoyannopoulos, G.; Chen, S.-H. and Fukui, M.: Liver alcohol dehydrogenase in Japanese: High population frequency of atypical form and its possible role in alcohol sensitivity. American Journal of Human Genetics 27: 789–796 (1975).PubMedGoogle Scholar
  156. Steegmüller, H.: On the geographical distribution of pseudoCholinesterase variants. Humangenetik 26: 167–185 (1975).PubMedGoogle Scholar
  157. Stewart, D.J.; Inaba, T.; Tang, B.K. and Kalow, W.: Hydrolysis of cocaine in human plasma by Cholinesterase. Life Sciences 20: 1557–1564 (1977).PubMedCrossRefGoogle Scholar
  158. Tang, B.K. and Carro-Ciampi, G.: A method for the study of N-glucosidation In vitro — amobarbital-N-glucoside formation in incubations with human liver. Biochemical Pharmacology 29: 2085–2088 (1980).PubMedCrossRefGoogle Scholar
  159. Tang, B.K.; Kalow, W.; Endrenyi, L. and Chan, F.Y.: An assessment of short-cut procedures for studying drug metabolism using amobarbital as model drug. European Journal of Clinical Pharmacology 22: 229–233 (1982).PubMedCrossRefGoogle Scholar
  160. Tang, B.K.; Kalow, W. and Grey, A.A.: Amobarbital metabolism in man: N-Glucoside formation. Research Communications in Chemical Pathology and Pharmacology 21: 45–53 (1978).PubMedGoogle Scholar
  161. Tang, B.K.; Kalow, W. and Grey, A.A.: Metabolic fate of phenobarbital in man: N-Glucoside formation. Drug Metabolism and Disposition 7: 315–318 (1979).PubMedGoogle Scholar
  162. Teng, Y.-S.; Jehan, S. and Lie-lnjo, L.E.: Human alcohol dehydrogenase ADH2 and ADH1 polymorphisms in ethnic Chinese and Indians of West Malaysia. Human Genetics 53: 87–90 (1979).PubMedCrossRefGoogle Scholar
  163. Testa, B. and Jenner, P.: Drug Metabolism: Chemical and Biochemical Aspects (Marcel Dekker Inc., New York 1976).Google Scholar
  164. Timbrell, J.A.; Mitchell, J.R.; Snodgrass, W.R. and Nelson, S.D.: Isoniazid hepatotoxicity: The relationship between covalent binding and metabolism in vivo.. Journal of Pharmacology and Experimental Therapeutics 213: 364–369 (1980).PubMedGoogle Scholar
  165. Valentino, R.J.; Lockridge, O.; Eckerson, H.W. and LaDu, B.N.: Prediction of drug sensitivity in individuals with atypical serum Cholinesterase based on in vitro biochemical studies. Biochemical Pharmacology 30: 1643–1649 (1981).PubMedCrossRefGoogle Scholar
  166. Van Boxtel, C.J.; Breimer, D.D. and Danhof, M.: Studies on the different metabolic pathways of antipyrine as a tool in the assessment of the activity of different drug metabolizing enzyme systems in man. British Journal of Pharmacology 68: 121P (1980).Google Scholar
  167. Vasko, M.R.; Bell, R.D.; Daly, D.D.; and Pippenger, C.E.: Inheritance of Phenytoin hypometabolism. A kinetic study of one family. Clinical Pharmacology and Therapeutics 27: 96–103 (1980).PubMedCrossRefGoogle Scholar
  168. Vesell, E.S.: Genetic and environmental factors affecting drug disposition in man. Clinical Pharmacology and Therapeutics 22: 659–679 (1977).PubMedGoogle Scholar
  169. Vesell, E.S.: The value of antipyrine and aminopyrine as model substrates in assessing drug-metabolizing capacity in man. Trends in Pharmacological Sciences 1 (No. 16) [Dec 1980].Google Scholar
  170. Vesell, E.S. and Page, J.G.. Genetic control of drug levels in man: Antipyrine. Science 161: 72–73 (1968).PubMedCrossRefGoogle Scholar
  171. Vestergaard, P. and Leverett, R.: Constancy of urinary Creatinine excretion. Journal of Laboratory and Clinical Medicine 51: 211–218 (1958).PubMedGoogle Scholar
  172. Viby-Mogensen, J. and Hanel, H.K.: Prolonged apnoea after suxamethonium. An analysis of the first 225 cases reported to the Danish Cholinesterase Research Unit. Acta Anaesthesiologica Scandinavica 22: 371–380 (1978).PubMedCrossRefGoogle Scholar
  173. Wiholm, B.-E.; Alvan, G.; Bertilsson, L.; Sawe, J. and Sjöqvist, F.: Hydroxylation of debrisoquine in patients with 1acticacidosis after phenformin. Lancet 1: 1098–1099 (1981).PubMedCrossRefGoogle Scholar
  174. Wartburg, J.P. von: Acetaldehyde; in Sandier (Ed.) Psychopharmacology of Alcohol, pp. 137–147 (Raven Press, New York 1980).Google Scholar
  175. Wartburg, J.-P. von; Papenberg, J. and Aebi, H.: An atypical human alcohol dehydrogenase. Canadian Journal of Biochemistry 43: 889–898 (1965).CrossRefGoogle Scholar
  176. Wartburg, J.P. von and Schürch, P.M.: Atypical human liver alcohol dehydrogenase. Annals of the New York Academy of Sciences 151: 936–946 (1968).Google Scholar
  177. Weinshilboum, R.M. and Raymond, F.A.: Inheritance of low erythrocyte catechol-0-methyltransferase activity in man. American Journal of Human Genetics 29: 125–135 (1977).PubMedGoogle Scholar
  178. Weinshilboum, R.M. and Sladek, S.L.: Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity. American Journal of Human Genetics 32: 651–662 (1980).PubMedGoogle Scholar
  179. Woolhouse, N.M.; Andoh, B.; Mahgoub, A.; Sloan, T.P.; Idle, J.R. and Smith R.L.: Debrisoquine hydroxylation polymorphism among Ghanaians and Caucasians. Clinical Pharmacology and Therapeutics 26: 584–591 (1979).PubMedGoogle Scholar
  180. Yang, C.S.: Interactions between cytochrome P-450 and NADPH-cytochrome P-450 reductase in the microsomal membrane; in Ullrich et al. (Eds) Microsomes and Drug Oxidations, pp. 9–16 (Pergamon Press, Oxford 1977).Google Scholar
  181. Zeiner, A.R. and Paredes, A.: Racial differences in arcadian variation of ethanol metabolism. Alcoholism: Clinical and Experimental Research 2: 71–75 (1978).CrossRefGoogle Scholar

Copyright information

© ADIS Press Australasia Pty Ltd. 1982

Authors and Affiliations

  • W. Kalow
    • 1
  1. 1.Department of PharmacologyUniversity of TorontoTorontoCanada

Personalised recommendations