European Journal of Clinical Pharmacology

, Volume 36, Issue 6, pp 537–547 | Cite as

Clinical significance of the sparteine/debrisoquine oxidation polymorphism

  • K. Brøsen
  • L. F. Gram
Special Articles


The sparteine/debrisoquine oxidation polymorphism results from differences in the activity of one isozyme of cytochrome P450, the P450db1 (P450 IID1). The oxidation of more than 20 clinically useful drugs has now been shown to be under similar genetic control to that of sparteine/debrisoquine. The clinical significance of this polymorphism may be defined by the value of phenotyping patients before treatment. The clinical significance of such polymorphic elimination of a particular drug can be analyzed in three steps: first, does the kinetics of active principle of a drug depend significantly on P450db1?; second, is the resulting pharmacokinetic variability of any clinical importance?; and third, can the variation in response be assessed by direct clinical or paraclinical measurements? It is concluded from such an analysis that, in general, the sparteine/debrisoquine oxidation polymorphism is of significance in patient management only for those drugs for which plasma concentration measurements are considered useful and for which the elimination of the drug and/or its active metabolite is mainly determined by P450db1. At present, this applies to tricyclic antidepressants and to certain neuroleptics (e.g. perphenazine and thioridazine) and antiarrhythmics (e.g. propafenone and flecainide). Phenotyping should be introduced in to clinical routine under strictly controlled conditions to afford a better understanding of its potentials and limitations. The increasing knowledge of specific substrates and inhibitors of P450db1 allows precise predictions of drug-drug interactions. At present, the strong inhibitory effect of neuroleptics on the metabolism of tricyclic antidepressants represents the best clinically documented and most relevant example of such an interaction.

Key words

sparteine debrisoquine pharmacogenetics oxidation polymorphism clinical significance oxidative drug metabolism genetic control 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alván G, Grind M, Graffner C, Sjöqvist F (1984) Relationship ofN-demethylation of amiflamine and its metabolite to debrisoquine hydroxylation polymorphism. Clin Pharmacol Ther 36: 515–519Google Scholar
  2. Back DJ, Maggs JL, Purba HS, Newby S, Park BK (1984) 2-Hydroxylation of ethinyloestradiol in relation to the oxidation of sparteine and antipyrine. Br J Clin Pharmacol 18: 603–607Google Scholar
  3. von Bahr C, Spina E, Birgersson C (1985) Inhibition of desmethylimipramine 2-hydroxolation by drugs in human liver microsomes. Biochem Pharmacol 14: 2501–2505Google Scholar
  4. von Bahr C, Guengerich FP, Morin G, Nordin C (1989) The use of human liver banks in pharmacogenetic research. In: Dahl SG, Gram LF (eds) Clinical pharmacology in psychiatry: From molecular studies to clinical reality. Springer, Berlin Heidelberg New York Tokyo (in press)Google Scholar
  5. Balant LP, Gundert-Remy U, Boobis AR, von Bahr C (1989) Genetic polymorphism in drug metabolism: Relevance for the development of new drugs. Eur J Clin Pharmacol (in press)Google Scholar
  6. Balant-Gorgia AE, Balant LP, Genet C, Dayer P, Aeschlimann JM, Garrone G (1986) Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolites. Eur J Clin Pharmacol 31: 449–455Google Scholar
  7. Baumann P, Jonzier-Perey M, Koeb L, Küpfer A, Tinguely D, Schöpf J (1986) Amitriptyline pharmacokinetics and clinical response: II. Metabolic polymorphism assessed by hydroxylation of debrisoquine and mephenytoin. Int Clin Psychopharmacol 1: 102–112Google Scholar
  8. Beckmann J, Hertrampf R, Gundert-Remy U, Mikus G, Gross AS, Eichelbaum M (1988) Is there a genetic factor in flecainide toxicity? Br Med J 297: 1316Google Scholar
  9. Beerahee M, Wilkins MR, Jack DB, Beevers DG, Kendall MJ (1987) Twelve hour (through) plasma nifedipine concentrations during chronic treatment with nifedipine retard. Eur J Clin Pharmacol 32: 347–349Google Scholar
  10. Bertilsson L, Eichelbaum M, Mellström B, Säwe J, Schulz H-U, Sjöqvist F (1980) Nortriptyline and antipyrine clearance in relation to debrisoquine hydroxylation in man. Life Sci 27: 1673–1677Google Scholar
  11. Bertilsson L, Åberg-Wistedt A (1983) The debrisoquine hydroxylation test predicts steady-state plasma levels of desipramine. Br J Clin Pharmacol 15: 388–390Google Scholar
  12. Bertilsson L, Åberg-Wistedt A, Gustafsson LL, Nordin C (1985) Extremely rapid hydroxylation of debrisoquine: A case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Ther Drug Monit 7: 478–480Google Scholar
  13. Bertilsson L, Henthorn TK, Sanch E, Tybring G, Säwe J, Villén T (1989) Importance of genetic factors in the regulation of diazepam metabolism: Relationship to S-mephenytoin, but not debrisoquine hydroxylation phenotype. Clin Pharmacol Ther (in press)Google Scholar
  14. Boobis AR, Murray S, Kahn GC, Robertz GM, Davies DS (1983) Substrate specificity of the form of cytochrome P-450 catalyzing the 4-hydroxylation of debrisoquine in man. Mol Pharmacol 23: 474–481Google Scholar
  15. Brinn R, Brøsen K, Gram LF, Haghfelt T, Otton SV (1986) Sparteine oxidation is practically abolished in quinidine-treated patients. Br J Clin Pharmacol 22: 194–197Google Scholar
  16. Brøsen K, Otton SV, Gram LF (1986a) Imipramine demethylation and hydroxylation: Impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 40: 543–549Google Scholar
  17. Brøsen K, Klysner R, Gram LF, Otton SV, Bech P, Bertilsson L (1986b) Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism. Eur J Clin Pharmacol 30: 679–684Google Scholar
  18. Brøsen K, Gram LF, Haghfelt T, Bertilsson L (1987) Extensive metabolizers of debrisoquine become poor metabolizer during quinidine treatment. Pharmacol Toxicol 60: 312–314Google Scholar
  19. Brøsen K, Gram LF (1988) First-pass metabolism of imipramine and desipramine: Impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 43: 400–406Google Scholar
  20. Clark DWJ, Morgan AKW, Waal-Manning H (1984) Adverse effects from metoprolol are not generally associated with oxidation status. Br J Clin Pharmacol 18: 965–967Google Scholar
  21. Cooper RG, Evans DAP, Price AH (1987) Studies on the metabolism of perhexiline in man. Eur J Clin Pharmacol 32: 569–576Google Scholar
  22. Dahl SG (1986) Plasma level monitoring of antipsychotic drugs. Clinical utility. Clin Pharmacokinet 11: 36–61Google Scholar
  23. Dahl-Puustinen ML, Lidén A, Alm C, Bertilsson L (1989) Disposition of perphenazine is related to the polymorphic debrisoquine hydroxylation in man. Clin Pharmacol Ther (in press)Google Scholar
  24. Dahlqvist R, Bertilsson L, Birkett DJ, Eichelbaum M, Säwe J, Sjöqvist F (1984) Theophylline metabolism in relation to antipyrine, debrisoquine, and sparteine metabolism. Clin Pharmacol Ther 35: 815–821Google Scholar
  25. Danhof M, Idle JR, Teunissen MWE, Sloan TP, Breimer DD, Smith RL (1981) Influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation. Pharmacology 22: 349–358Google Scholar
  26. Dayer P, Balant L, Kupfer A, Striberni R, Leemann T (1985) Effect of oxidative polymorphism (debrisoquine/sparteine type) on hepatic first-pass metabolism of bufuralol. Eur J Clin PHarmacol 28: 317–320Google Scholar
  27. Dayer P, Desmeules J, Leemann T, Striberni R (1988) Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation. Biochem Biophys Res Commun 152: 411–416Google Scholar
  28. Dayer P, Gasser R, Gut J, Kronbach T, Robertz GM, Eichelbaum M, Meyer UA (1984) Characterization of a common genetic defect of cytochrome P450 function (debrisoquine-sparteine type of polymorphism). Biochem Biophys Res Commun 125: 374–380Google Scholar
  29. Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ (1979a) DefectiveN-oxidation of sparteine in man: A new pharmacogenetic defect. Eur J Clin Pharmacol 16: 183–187Google Scholar
  30. Eichelbaum M, Spannbrucker N, Dengler HJ (1979b) Influence of the defective metabolism of sparteine on its pharmacokinetics. Eur J Clin Pharmacol 16: 189–194Google Scholar
  31. Eichelbaum M, Bertilsson L, Säwe J, Zekorn C (1982) Polymorphic oxidation of sparteine and debrisoquine: Related pharmacogenetic entities. Clin Pharmacol Ther 31: 184–186Google Scholar
  32. Eichelbaum M, Tomson T, Tybring G, Bertilsson L (1985) Carbamazepine metabolism in man. Induction and pharmacogenetic aspects. Clin Pharmacokinet 10: 80–90Google Scholar
  33. Eichelbaum M, Mineshita S, Ohnhaus EE, Zekorn C (1986) The influence of enzyme induction on polymorphic sparteine oxidation. Br J Clin Pharmacol 22: 49–53Google Scholar
  34. Evans DAP, Mahgoub A, Sloan TP, Idle JR, Smith RL (1980) A family and population study of genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet 17: 102–105Google Scholar
  35. Fonne-Pfister R, Meyer UA (1988) Xenobiotic and endobiotic inhibitors of cytochrome P-450db1 function, the target of the debrisoquine/sparteine type polymorphism. Biochem Pharmacol 37: 3829–3855Google Scholar
  36. Frielle T, Collins S, Daniel KW, Caron MG, Lefkowitz RJ (1987) Cloning of the cDNA for the human β1-adrenergic receptor. Proc Natl Acad Sci USA 84: 7920–7924Google Scholar
  37. Gabris G, Baumann P, Jonzier-Perey M, Bosshart P, Woggon B, Küpfer A (1985) N-Methylation of maprotiline in debrisoquine/mephenytoin-phenotyped depressive patients. Biochem Pharmacol 34: 409–410Google Scholar
  38. Gleiter CH, Aichele G, Nilsson E, Hengen N, Antonin KH, Bieck PR (1985) Discovery of altered pharmacokinetics of CGP 15 210 G in poor hydroxylators of debrisoquine during early drug development. Br J Clin Pharmacol 20: 81–84Google Scholar
  39. Gonzalez FJ, Skoda R, Kimura S, Umeno M, Zanger UM, Nebert DW, Gelboin HV, Hardwick JP, Meyer UA (1988) Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331: 442–446Google Scholar
  40. Gram LF (1975) Effects of perphenazine on imipramine metabolism in man. Psychopharmacol Commun 1: 165–175Google Scholar
  41. Gram LF, Brøsen K (1989) Inhibitors of the microsomal oxidation of psychotropic drugs: Selectivity and clinical significance. In: Dahl SG, Gram LF (eds) Clinical pharmacology in psychiatry: From molecular studies to clinical reality. Springer, Berlin Heidelberg New York Tokyo (in press)Google Scholar
  42. Gram LF, Debruyne D, Caillard V, Boulenger JP, Lacotte J, Moulin M, Zarifian E (1989) Substantial rise in sparteine metabolic ratio during haloperidol treatment. Br J Clin Pharmacol 27: 272–275Google Scholar
  43. Gram LF, Kragh-Sørensen P, Kristensen CB, Møller M, Pedersen OL, Thayssen P (1984) Plasma level monitoring of antidepressants: Theoretical basis and clinical application. In: Usdin E, Åsberg M, Bertilsson L, Sjöqvist F (eds) Frontiers in biochemical and pharmacological research in depression. Raven Press, New York, pp 399–411Google Scholar
  44. Gram LF, Overø KF (1972) Drug interaction: Inhibitory of neuroleptics on metabolism of tricyclic antidepressants in man. Br Med J 163: 463–465Google Scholar
  45. Hirschowitz J, Bennet JA, Semian FP, Garber D (1983) Thioridazine effect on desipramine plasma levels. J Clin Psychopharmacol 3: 376–379Google Scholar
  46. Inaba T, Jurima M, Mahon WA, Kalow W (1985) In vitro studies of two isozymes of human liver cytochrome P-450-mephenytoin hydroxylase and sparteine monooxygenase. Drug Metab Dispos 13: 443–448Google Scholar
  47. Inaba T, Otton SV, Kalow W (1980) Deficient metabolism of sparteine and debrisoquine. Clin Pharmacol Ther 27: 547–549Google Scholar
  48. Iyun AO, Lennard MS, Tucker GT, Woods HF (1986) Metoprolol and debrisoquin metabolism in Nigerians: Lack of evidence for polymorphic oxidation. Clin Pharmacol Ther 40: 387–394Google Scholar
  49. Jackson PR, Tucker GT, Lennard MS, Woods HF (1986) Polymorphic drug oxidation: pharmacokinetic basis and comparison of experimental indices. Br J Pharmacol 22: 541–550Google Scholar
  50. Kitchen I, Tremblay J, André, Dring LG, Idle JR, Smith RL, Williams RT (1979) Interindividual and interspecies variation in the metabolism of the hallucinogen 4-methoxyamphetamine. Xenobiotica 7: 397–404Google Scholar
  51. Knodell RG, Raghvendra KD, Wilkinson GR, Guengerich FP (1988) Oxidative metabolism of hexobarbital in human liver: Relationship to polymorphic S-mephenytoin 4-hydroxylation. J Pharmacol Exp Ther 245: 845–849Google Scholar
  52. Kroemer HK, Mikus G, Kronbach T, Meyer UA, Eichelbaum M (1989) In vitro characterization of the human cytochrome P-450 involved in polymorphic oxidation of propafenone. Clin Pharmacol Ther 45: 28–33Google Scholar
  53. Kronbach T, Fisher V, Meyer UA (1988) Cyclosporine metabolism in human liver: Identification of a cytochrome P450III gene family as the major cyclosporine metabolizing enzyme explaining interactions of cyclosporine with other drugs. Clin Pharmacol Ther 43: 630–635Google Scholar
  54. Küpfer A, Preisig R (1984) Pharmacogenetics of mephenytoin: A new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 26: 753–759Google Scholar
  55. Küpfer A, Branch RA (1985) Stereoselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation. Clin Pharmacol Ther 38: 414–418Google Scholar
  56. Leemann TP, Dayer P, Meyer UA (1986) Single-dose quinidine treatment inhibits metoprolol oxidation in extensive metabolizers. Eur J Clin Pharmacol 29: 739–741Google Scholar
  57. Lennard MS, Tucker GT, Silas JH, Freestone S, Ramsay LE, Woods HF (1983) Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolizers. Clin Pharmacol Ther 34: 732–737Google Scholar
  58. Lennard MS, Jackson PR, Freestone S, Tucker GT, Ramsay LE, Woods HF (1984) The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol. Br J Clin Pharmacol 17: 679–685Google Scholar
  59. Lennard MS, McGourty JC, Silas JH (1988) Lack of relationship between debrisoquine oxidation phenotype and the pharmacokinetics and first dose effect of prazosin. Br J Clin Pharmacol 25: 276–278Google Scholar
  60. Lewis RV, Lennard MS, Jackson PR, Tucker GT, Ramsay LE, Woods HF (1985) Timolol and atenolol: relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics. Br J Clin Pharmacol 19: 329–333Google Scholar
  61. Lou YC, Ying L, Bertilsson L, Sjöqvist F (1987) Low frequency of slow debrisoquine hydroxylation in a native Chinese population. Lancet 2: 852–853Google Scholar
  62. Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet 2: 584–586Google Scholar
  63. Mellström B, Bertilsson L, Lou Y-C, Säwe J, Sjöqvist F (1983) Amitriptyline metabolism: Relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 34: 516–520Google Scholar
  64. Meyer UA, Gut J, Kronbach T, Skoda C, Meier UT, Catin T (1986) The molecular mechanisms of two common polymorphisms of drug oxidation — evidence for functional changes in cytochrome P-450 isozymes catalysing bufuralol and mephenytoin oxidation. Xenobiotica 16: 449–464Google Scholar
  65. Mikus G, Ha HR, Vozeh S, Zekorn F, Follath F, Eichelbaum M (1986) Pharmacokinetics and metabolism of quinidine in extensive and poor metabolizers of sparteine. Eur J Clin Pharmacol 31: 69–72Google Scholar
  66. Miners JO, Wing LMH, Birkett DJ (1985) Normal metabolism of debrisoquine and theophylline in a slow tolbutamide metaboliser. Austr NZ J Med 15: 348–349Google Scholar
  67. Nakamura K, Goto F, Ray WA, McAllister CB, Jacqz E, Wilkinson GR, Branch RA (1985) Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 38: 402–408Google Scholar
  68. Nebert DW, Adesnik M, Coon MJ, Estabrook RW, Gonzalez FJ, Guengerich FP, Gonsalus IC, Johnson EF, Kemper B, Levin W, Phillips IR, Sato R, Waterman MR (1987) The P450 gene super family: Recommended nomenclature. DNA 6: 1–11Google Scholar
  69. Nordin C, Siwers B, Benitz J, Bertilsson L (1985) Plasma concentrations of nortriptyline and its 10-hydroxymetabolite in depressed patients-relationship to the debrisoquine hydroxylation metabolic ratio. Br J Clin Pharmacol 19: 832–835Google Scholar
  70. Oates NS, Shah RR, Idle JR, Smith RL (1983) Influence of oxidation polymophism on phenformin kinetics and dynamics. Clin Pharmacol Ther 34: 827–834Google Scholar
  71. Oram M, Wilson K, Burnett D, Al-Dabbagh SG, Idle JR, Smith RL (1982) Metabolic oxidation of methaqualone in extensive and poor metabolizers of debrisoquine. Eur J Clin Pharmacol 23: 147–150Google Scholar
  72. Otton SV, Inaba T, Kalow W (1984) Competitive inhibition of sparteine oxidation in human liver by β-adrenoceptor antagonists and other cardiovascular drugs. Life Sci 34: 73–80Google Scholar
  73. Pierce DM, Smith SE, Franklin RA (1987) The pharmacokinetics of indoramin and 6-hydroxyindoramin in poor and extensive hydroxylators of debrisoquine. Eur J Clin Pharmacol 33: 59–65Google Scholar
  74. Preskorn S (1989) Therapeutic drug monitoring of tricyclic antidepressants: A means of avoiding toxicity. In: Dahl SG, Gram LF (eds) Clinical pharmacology in psychiatry. From molecular studies to clinical reality. Springer, Berlin Heidelberg New York Tokyo, in pressGoogle Scholar
  75. Roy SD, Hawes EM, McKay G, Korchinski ED, Midha KK (1985) Metabolism of methoxyphenamine in extensive and poor metabolizers of debrisoquin. Clin Pharmacol Ther 38: 128–133Google Scholar
  76. Schmid B, Bircher J, Preisig R, Küpfer A (1985) Polymorphic dextromethorphan metabolism: Co-segretation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther 38: 618–624Google Scholar
  77. Shaheen O, Patel J, Avant GR, Hamilton M, Wood AJJ (1986) Effect of cirrhosis and debrisoquin phenotype on the disposition and effects of pinacidil. Clin Pharmacol Ther 40: 650–655Google Scholar
  78. Siddoway LA, Thompson KA, McAllister CB, Wang T, Wilkinson GR, Roden DM, Woosley RL (1987) Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 75: 785–791Google Scholar
  79. Siris SG, Cooper TB, Rifbein AE, Brenner R, Liebermann JA (1982) Plasma imipramine concentration in patients receiving concomitant fluphenazine decanoate. Am J Psychiatry 139: 104–106Google Scholar
  80. Sjöqvist F, Bertilsson L (1986) Slow hydroxylation of tricylic anti-depressants — Relationship to polymorphic drug oxidation. In: Kalow W, Goedde HW, Agarwal DP (eds) Ethnic differences in reactions to drugs and xenobiotics. Alan R. Liss, New York, pp 169–188Google Scholar
  81. Sloan TP, Mahgoub A, Lancaster R, Idle JR, Smith RL (1978) Polymorphism of carbon oxidation of drugs and clinical implications. Br Med J 2: 655–657Google Scholar
  82. Sloan TP, Lancaster R, Shah RR, Idle JR, Smith RL (1983) Genetically determined oxidation capacity and the disposition of debrisoquine. Br J Clin Pharmacol 15: 443–450Google Scholar
  83. Speirs CJ, Murray S, Boobis AR, Seddon CE, Davies DS (1986) Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine. Br J Clin Pharmacol 22: 739–743Google Scholar
  84. Steiner E, Iselius L, Alván G, Lindsten J, Sjöqvist F (1985) A family study of genetic and environmental factors determining polymorphic hydroxylation of debrisoquin. Clin Pharmacol Ther 38: 394–401Google Scholar
  85. Steiner E, Alván G, Garle M, Maguire JH, Lind M, Nilson S-O, Tomson T, McClanahan JS, Sjöqvist F (1987) The debrisoquin hydroxylation phenotype does not predict the metabolism of phenytoin. Clin Pharmacol Ther 42: 326–333Google Scholar
  86. Steiner E, Dumont E, Spina E, Dahlqvist R (1988a) Inhibition of desipramine 2-hydroxylation by quinidine and quinine. Clin Pharmacol Ther 43: 577–581Google Scholar
  87. Steiner E, Bertilsson L, Säwe J, Bertling I, Sjöqvist F (1988b) Polymorphic debrisoquine hydroxylation in 757 Swedish subjects. Clin Pharmacol Ther 44: 431–435Google Scholar
  88. Syvählahti EKG, Lindberg R, Kallio J, de Vocht M (1986) Inhibitory effects of neuroleptics on debrisoquine oxidation in man. Br J Clin Pharmacol 22: 89–92Google Scholar
  89. Wagner F, Kalusche D, Trenk D, Jänchen E, Roskamm H (1987a) Drug interaction between propafenone and metoprolol. Br J Clin Pharmacol 24: 213–220Google Scholar
  90. Wagner F, Jänchen E, Trenk D (1987b) Severe complications of antianginal drug therapy in a patient identified as a poor metabolizer of metoprolol, propafenone, diltiazem and sparteine. Klin Wochenschr 65: 1164–1168Google Scholar
  91. Wang T, Roden DM, Wolfenden HT, Woosley RL, Wood AJJ, Wilkinson GR (1984) Influence of genetic polymorphism on the metabolism and disposition of encainide in man. J Pharmacol Exp Ther 228: 605–611Google Scholar
  92. Webb NR, Rose TM, Malik N, Marquardt H, Shoyab M, Todaro GJ, Lee DC (1987) Bovine and human cDNA sequences encoding a putative benzodiazepine receptor ligand. DNA 6: 71–79Google Scholar
  93. Zanger UM, Vilbois F, Hardwick J, Meyer UA (1988) Absence of hepatic cytochrome P450buf I causes genetically deficient debrisoquine oxidation in man. Biochemistry 27: 5447–5454Google Scholar
  94. Zekorn C, Achtert G, Hausleiter HJ, Moon CH, Eichelbaum M (1985) Pharmacokinetics of N-propylajmaline in relation to polymorphic sparteine oxidation. Klin Wochenschr 63: 1180–1186Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • K. Brøsen
    • 1
  • L. F. Gram
    • 1
  1. 1.Department of Clinical PharmacologyOdense UniversityOdenseDenmark

Personalised recommendations