Impact of P450 genetic polymorphism on the first-pass extraction of cardiovascular and neuroactive drugs

Advanced Drug Delivery Reviews

Volumn 27, Issue 2-3, 1997, Pages 171-199

  Fromm, Martin F ^a   Kroemer, Heyo K ^a   Eichelbaum, Michel ^a,b  

^a DR MARGARETE FISCHER BOSCH INSTITUTE OF CLINICAL PHARMACOLOGY   (Germany)

^b UNIVERSITY OF TÜBINGEN   (Germany)

Author keywords

Altered drug effects; CYP2C19; CYP2D6; Debrisoquine; Mephenytoin; Molecular basis; Review; Sparteine; Variable pharmacokinetics

Indexed keywords

DRUG THERAPY; ENZYMES; EXTRACTION; HEALTH RISKS; METABOLISM; MUTAGENESIS; PHARMACOKINETICS; PROTEINS; TOXICITY;

DEBRISOQUINE; MEPHENYTOIN; POLYMORPHIC ENZYMES; SPARTEINE;

DRUG INTERACTIONS;

ANTIARRHYTHMIC AGENT; ANTIDEPRESSANT AGENT; BUFURALOL; CARDIOVASCULAR AGENT; CLOMIPRAMINE; CYTOCHROME P450; CYTOCHROME P450 ISOENZYME; DEBRISOQUINE; DESIPRAMINE; DEXTROMETHORPHAN; ENCAINIDE; FLECAINIDE; FLUVOXAMINE; HALOPERIDOL; IMIPRAMINE; MEPHENYTOIN; METOPROLOL; MEXILETINE; NEUROLEPTIC AGENT; NORTRIPTYLINE; OPIATE; PAROXETINE; PERHEXILINE; PROPAFENONE; PROPRANOLOL; QUINIDINE; SPARTEINE; THIORIDAZINE; TIMOLOL; UNINDEXED DRUG;

DRUG CLEARANCE; DRUG DISPOSITION; DRUG METABOLISM; FIRST PASS EFFECT; GENETIC POLYMORPHISM; HUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW;

EID: 0342981500     PISSN: 0169409X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0169-409X(97)00042-2     Document Type: Review

References (239)

1. Kroemer H.K., Eichelbaum M. "It's the genes, stupid". Molecular basis and clinical consequences of genetic cytochrome P450 2D6 polymorphism. Life Sci. 56:1995;2285-2298.
2. Siddoway L.A., Thompson K.A., McAllister C.B., Wang T., Wilkinson G.R., Roden D.M., Woosley R.L. Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation. 75:1987;785-791.
3. Kroemer H.K., Mikus G., Kronbach T., Meyer U.A., Eichelbaum M. In vitro characterization of the human cytochrome P-450 involved in polymorphic oxidation of propafenone. Clin. Pharmacol. Ther. 45:1989;28-33.
4. Eichelbaum M., Spannbrucker N., Steincke B., Dengler H.J. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur. J. Clin. Pharmacol. 16:1979;183-187.
5. Bock K.W., Schrenk D., Forster A., Griese E.-U., Mörike K., Brockmeier D., Eichelbaum M. The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes. Pharmacogenetics. 4:1994;209-218.
6. Mahgoub A., Idle J.R., Dring L.G., Lancaster R., Smith R.L. Polymorphic hydroxylation of debrisoquine in man. Lancet. 2:1977;584-586.
7. Tucker G.T., Silas J.H., Iyun A.O., Lennard M.S., Smith A.J. Polymorphic hydroxylation of debrisoquine. Lancet. 2:1977;718.
8. Evans D.A., Mahgoub A., Sloan T.P., Idle J.R., Smith R.L. A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J. Med. Genet. 17:1980;102-105.
9. Eichelbaum M., Bertilsson L., Säwe J., Zekorn C. Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities. Clin. Pharmacol. Ther. 31:1982;184-186.
10. Jacqz-Aigrain E., Funck-Brentano C., Cresteil T. CYP2D6- and CYP3A-dependent metabolism of dextromethorphan in humans. Pharmacogenetics. 3:1993;197-204.
11. Meyer U.A., Zanger U.M. Molecular mechanisms of genetic polymorphisms of drug metabolism. Ann. Rev. Pharmacol. Toxicol. 37:1997;269-296.
12. Eichelbaum M., Baur M.P., Dengler H.J., Osikowska-Evers B.O., Tieves G., Zekorn C., Rittner C. Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22. Br. J. Clin. Pharmacol. 23:1987;455-458.
13. Gonzalez F.J., Vilbois F., Hardwick J.P., McBride O.W., Nebert D.W., Gelboin H.V., Meyer U.A. Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Genomics. 2:1988;174-179.
14. Kimura S., Umeno M., Skoda R.C., Meyer U.A., Gonzalez F.J. 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. 45:1989;889-904.
15. Daly A.K., Brockmöller J., Broly F., Eichelbaum M., Evans W.E., Gonzalez F.J., Huang J.-D., Idle J.R., Ingelman-Sundberg M., Ishizaki T., Jacqz-Aigrain E., Meyer U.A., Nebert D.W., Steen V.M., Wolf C.R., Zanger U.M. Nomenclature for human CYP2D6 alleles. Pharmacogenetics. 6:1996;193-201.
16. Stüven T., Griese E.-U., Kroemer H.K., Eichelbaum M., Zanger U.M. Rapid detection of CYP2D6 null alleles by long distance- and multiplex-polymerase chain reaction. Pharmacogenetics. 6:1996;417-421.
17. Broly F., Gaedigk A., Heim M., Eichelbaum M., Mörike K., Meyer U.A. Debrisoquine/sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population. DNA Cell Biol. 10:1991;545-558.
18. Brøsen K., Nielsen P.N., Brusgaard K., Gram L.F., Skodt K. CYP2D6 genotype determination in the Danish population. Eur. J. Clin. Pharmacol. 47:1994;221-225.
19. Johansson I., Oscarson M., Yue Q.-Y., Bertilsson L., Sjöqvist F., Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: Characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol. Pharmacol. 46:1994;452-459.
20. Wang S.L., Huang J.D., Lai M.D., Liu B.H., Lai M.L. Molecular basis of genetic variation in debrisoquine hydroxylation in Chinese subjects: Polymorphism in RFLP and DNA sequence of CYP2D6. Clin. Pharmacol. Ther. 53:1993;410-418.
21. Armstrong M., Fairbrother K., Idle J.R., Daly A.K. The cytochrome P450 CYP2D6 allelic variant CYP2D6J and related polymorphisms in a European population. Pharmacogenetics. 4:1994;73-81.
22. Yokota H., Tamura S., Furuya H., Kimura S., Watanabe M., Kanazawa I., Kondo I., Gonzalez F.J. Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism. Pharmacogenetics. 3:1993;256-263.
23. Bertilsson L., Aberg-Wistedt A., Gustafsson L.L., Nordin C. Extremely rapid hydroxylation of debrisoquine: a case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Ther. Drug Monit. 7:1985;478-480.
24. Bertilsson L., Dahl M.L., Sjöqvist F., Aberg-Wistedt A., Humble M., Johansson I., Lundqvist E., Ingelman-Sundberg M. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet. 341:1993;63.
25. Johansson I., Lundqvist E., Bertilsson L., Dahl M.L., Sjöqvist F., Ingelman-Sundberg M. 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. 90:1993;11825-11829.
26. Dahl M.L., Johansson I., Bertilsson L., Ingelman-Sundberg M., Sjöqvist F. Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J. Pharmacol. Exp. Ther. 274:1995;516-520.
27. Agundez J.A.G., Ledesma M.C., Ladero J.M., Benitez J. Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population. Clin. Pharmacol. Ther. 57:1995;265-269.
28. Aklillu E., Persson I., Bertilsson L., Rodriques F., Ingelman-Sundberg M. Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated function CYP2D6 alleles. J. Pharmacol. Exp. Ther. 278:1996;441-446.
29. Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin. Pharmacokinet. 29:1995;192-209.
30. Kolars J.C., Awni W.M., Merion R.M., Watkins P.B. First-pass metabolism of cyclosporine by the gut. Lancet. 338:1991;1488-1490.
31. Thummel K.E., O'Shea D., Paine M.F., Shen D.D., Kunze K.L., Perkins J.D., Wilkinson G.R. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin. Pharmacol. Ther. 59:1996;491-502.
32. Fromm M.F., Busse D., Kroemer H.K., Eichelbaum M. Differential induction of prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology. 24:1996;796-801.
33. Hebert M.F., Roberts J.P., Prueksaritanont T., Benet L.Z. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin. Pharmacol. Ther. 52:1992;453-457.
34. Ducharme M.P., Warbasse L.H., Edwards D.J. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin. Pharmacol. Ther. 57:1995;485-491.
35. De Waziers I., Cugnenc P.H., Yang C.S., Leroux J.-P., Beaune P.H. Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. J. Pharmacol. Exp. Ther. 253:1990;387-394.
36. Prueksaritanont T., Dwyer L.M., Cribb A.E. (+)-Bufuralol 1′-hydroxylation activity in human and rhesus monkey intestine and liver. Biochem. Pharmacol. 50:1995;1521-1525.
37. Wagner F., Kalusche D., Trenk D., Jähnchen E., Roskamm H. Drug interaction between propafenone and metoprolol. Br. J. Clin. Pharmacol. 24:1987;213-220.
38. Engel G., Hofmann U., Kroemer H.K. Prediction of CYP2D6-mediated polymorphic drug metabolism (sparteine type) based on in vitro investigations. J. Chromatogr. B: Biomed. Appl. 678:1996;93-103.
39. Lennard M.S., Silas J.H., Freestone S., Ramsay L.E., Tucker G.T., Woods H.F. Oxidation phenotype - a major determinant of metoprolol metabolism and response. New Engl. J. Med. 307:1982;1558-1560.
40. McGourty J.C., Silas J.H., Lennard M.S., Tucker G.T., Woods H.F. Metoprolol metabolism and debrisoquine oxidation polymorphism - population and family studies. Br. J. Clin. Pharmacol. 20:1985;555-566.
41. Kirch W., Ohnhaus E.E., Zekorn C., Eichelbaum M., Spahn H., Mutschler E. Pharmacokinetics of metoprolol in relation to polymorphic sparteine oxidation. Arch. Toxicol. Suppl. 8:1985;401-402.
42. Laurent-Kenesi M.A., Funck-Brentano C., Poirier J.M., Decolin D., Jaillon P. Influence of CYP2D6-dependent metabolism on the steady-state pharmacokinetics and pharmacodynamics of metoprolol and nicardipine, alone and in combination. Br. J. Clin. Pharmacol. 36:1993;531-538.
43. Otton S.V., Crewe H.K., Lennard M.S., Tucker G.T., Woods H.F. Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes. J. Pharmacol. Exp. Ther. 247:1988;242-247.
44. Lennard M.S. The polymorphic oxidation of beta-adrenoceptor antagonists. Pharmacol. Ther. 41:1989;461-477.
45. Rowland K., Ellis S.W., Lennard M.S., Tucker G.T. Variable contribution of CYP2D6 to the N-dealkylation of S-(-)-propranolol by human liver microsomes. Br. J. Clin. Pharmacol. 42:1996;390-393.
46. Lennard M.S., Jackson P.R., Freestone S., Ramsay L.E., Tucker G.T., Woods H.F. The oral clearance and beta-adrenoceptor antagonist activity of propranolol after single dose are not related to debrisoquine oxidation phenotype. Br. J. Clin. Pharmacol. 17(Suppl. 1):1984;106S-107S.
47. Raghuram T.C., Koshakji R.P., Wilkinson G.R., Wood A.J. Polymorphic ability to metabolize propranolol alters 4-hydroxypropranolol levels but not beta blockade. Clin. Pharmacol. Ther. 36:1984;51-56.
48. Ward S.A., Walle T., Walle U.K., Wilkinson G.R., Branch R.A. Propranolol's metabolism is determined by both mephenytoin and debrisoquine hydroxylase activities. Clin. Pharmacol. Ther. 45:1989;72-79.
49. Lewis R.V., Lennard M.S., Jackson P.R., Tucker G.T., Ramsay L.E., Woods H.F. Timolol and atenolol: relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics. Br. J. Clin. Pharmacol. 19:1985;329-333.
50. Lennard M.S., Lewis R.V., Braun L.A., Ramsay L.E., Jackson P.R., Tucker G.T., Woods H.F. Timolol metabolism and debrisoquine oxidation phenotype - a population study. Br. J. Clin. Pharmacol. 23:1987;644P.
51. McGourty J.C., Silas J.H., Fleming J.J., McBurney A., Ward J.W. Pharmacokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquine. Clin. Pharmacol. Ther. 38:1985;409-413.
52. Nelson W.L., Fraunfelder F.T., Sills J.M., Arrowsmith J.B., Kuritsky J.N. Adverse respiratory and cardiovascular events attributed to timolol ophthalmic solution, 1978-1985. Am. J. Ophthalmol. 102:1986;606-611.
53. Eichelbaum M., Gross A. Stereochemical aspects of drug action and disposition. Adv. Drug Res. 28:1996;1-64.
54. Edeki T.I., He H., Wood A.J.J. Pharmacogenetic explanation for excessive beta-blockade following timolol eye drops: Potential for oral-ophthalmic drug interaction. J. Am. Med. Assoc. 274:1995;1611-1613.
55. Dayer P., Kubli A., Küpfer A., Courvoisier F., Balant L., Fabre J. Defective hydroxylation of bufuralol associated with side-effects of the drug in poor metabolisers. Br. J. Clin. Pharmacol. 13:1982;750-752.
56. Dayer P., Balant L., Küpfer A., Courvoisier F., Fabre J. Contribution of the genetic status of oxidative metabolism to variability in the plasma concentrations of beta-adrenoceptor blocking agents. Eur. J. Clin. Pharmacol. 24:1983;797-799.
57. Dayer P., Balant L., Küpfer A., Striberni R., Leemann T. Effect of oxidative polymorphism (debrisoquine/sparteine type) on hepatic first-pass metabolism of bufuralol. Eur. J. Clin. Pharmacol. 28:1985;317-320.
58. Echt D.S., Liebson P.R., Mitchell L.B., Peters R.W., Obias-Manno D., Barker A.H., Arensberg D., Baker A., Friedman L., Greene H.L., Huther M.L., Richardson D.W. the CAST investigators. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. New Engl. J. Med. 324:1991;781-788.
59. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. New Engl. J. Med. 321 (1989) 406-412.
60. Buchert E., Woosley R.L. Clinical implications of variable antiarrhythmic drug metabolism. Pharmacogenetics. 2:1992;2-11.
61. Eichelbaum M., Spannbrucker N., Dengler H.J. Influence of the defective metabolism of sparteine on its pharmacokinetics. Eur. J. Clin. Pharmacol. 16:1979;189-194.
62. Eichelbaum M., Reetz K.P., Schmidt E.K., Zekorn C. The genetic polymorphism of sparteine metabolism. Xenobiotica. 16:1986;465-481.
63. Eichelbaum M., Gross A.S. The genetic polymorphism of debrisoquine/sparteine metabolism - clinical aspects. Pharmacol. Ther. 46:1990;377-394.
64. Funck-Brentano C., Kroemer H.K., Lee J.T., Roden D.M. Propafenone. New Engl. J. Med. 322:1990;518-525.
65. Kroemer H.K., Funck-Brentano C., Silberstein D.J., Wood A.J., Eichelbaum M., Woosley R.L., Roden D.M. Stereoselective disposition and pharmacologic activity of propafenone enantiomers. Circulation. 79:1989;1068-1076.
66. Lee J.T., Kroemer H.K., Silberstein D.J., Funck-Brentano C., Lineberry M.D., Wood A.J., Roden D.M., Woosley R.L. The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone. New Engl. J. Med. 322:1990;1764-1768.
67. Kroemer H.K., Fischer C., Meese C.O., Eichelbaum M. Enantiomer/enantiomer interaction of (S)- and (R)-propafenone for cytochrome P450IID6-catalyzed 5-hydroxylation: in vitro evaluation of the mechanism. Mol. Pharmacol. 40:1991;135-142.
68. Kroemer H.K., Fromm M.F., Bühl K., Terefe H., Blaschke G., Eichelbaum M. An enantiomer-enantiomer interaction of (S)- and (R)-propafenone modifies the effect of racemic drug therapy. Circulation. 89:1994;2396-2400.
69. UK Propafenone PSVT Study Group. A randomized, placebo-controlled trial of propafenone in the prophylaxis of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation. Circulation 92 (1995) 2550-2557.
70. Wang T., Roden D.M., Wolfenden H.T., Woosley R.L., Wood A.J., Wilkinson G.R. Influence of genetic polymorphism on the metabolism and disposition of encainide in man. J. Pharmacol. Exp. Ther. 228:1984;605-611.
71. Roden D.M., Duff H.J., Altenbern D., Woosley R.L. Antiarrhythmic activity of the O-demethyl metabolite of encainide. J. Pharmacol. Exp. Ther. 221:1982;552-557.
72. Woosley R.L., Roden D.M., Dai G.H., Wang T., Altenbern D., Oates J., Wilkinson G.R. Co-inheritance of the polymorphic metabolism of encainide and debrisoquine. Clin. Pharmacol. Ther. 39:1986;282-287.
73. Woosley R.L., Wood A.J., Roden D.M. Drug therapy. Encainide. New Engl. J. Med. 318:1988;1107-1115.
74. Funck-Brentano C., Thomas G., Jacqz-Aigrain E., Poirier J.M., Simon T., Bereziat G., Jaillon P. Polymorphism of dextromethorphan metabolism: Relationships between phenotype, genotype and response to the administration of encainide in humans. J. Pharmacol. Exp. Ther. 263:1992;780-786.
75. Mikus G., Gross A.S., Beckmann J., Hertrampf R., Gundert-Remy U., Eichelbaum M. The influence of the sparteine/debrisoquine phenotype on the disposition of flecainide. Clin. Pharmacol. Ther. 45:1989;562-567.
76. Gross A.S., Mikus G., Fischer C., Hertrampf R., Gundert-Remy U., Eichelbaum M. Stereoselective disposition of flecainide in relation to the sparteine/debrisoquine metaboliser phenotype. Br. J. Clin. Pharmacol. 28:1989;555-566.
77. Gross A.S., Mikus G., Fischer C., Eichelbaum M. Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH. Eur. J. Clin. Pharmacol. 40:1991;155-162.
78. Funck-Brentano C., Becquemont L., Kroemer H.K., Bühl K., Knebel N.G., Eichelbaum M., Jaillon P. Variable disposition kinetics and electrocardiographic effects of flecainide during repeated dosing in humans: Contribution of genetic factors, dose-dependent clearance, and interaction with amiodarone. Clin. Pharmacol. Ther. 55:1994;256-269.
79. Evers J., Eichelbaum M., Kroemer H.K. Unpredictability of flecainide plasma concentrations in patients with renal failure: Relationship to side effects and sudden death? Ther. Drug Monit. 16:1994;349-351.
80. Turgeon J., Fiset C., Giguere R., Gilbert M., Mörike K., Rouleau J.R., Kroemer H.K., Eichelbaum M., Grech-Belanger O., Belanger P.M. Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man. J. Pharmacol. Exp. Ther. 259:1991;789-798.
81. Broly F., Vandamme N., Libersa C., Lhermitte M. The metabolism of mexiletine in relation to the debrisoquine/sparteine-type polymorphism of drug oxidation. Br. J. Clin. Pharmacol. 32:1991;459-466.
82. Broly F., Libersa C., Lhermitte M., Dupuis B. Inhibitory studies of mexiletine and dextromethorphan oxidation in human liver microsomes. Biochem. Pharmacol. 39:1990;1045-1053.
83. Broly F., Libersa C., Lhermitte M. Mexiletine metabolism in vitro by human liver. Drug Metab. Dispos. Biol. Fate Chem. 18:1990;362-368.
84. Lledo P., Abrams S.M.L., Johnston A., Patel M., Pearson R.M., Turner P. Influence of debrisoquine hydroxylation phenotype on the pharmacokinetics of mexiletine. Eur. J. Clin. Pharmacol. 44:1993;63-67.
85. Zekorn C., Achtert G., Hausleiter H.J., Moon C.H., Eichelbaum M. Pharmacokinetics of N-propylajmaline in relation to polymorphic sparteine oxidation. Klin. Wochenschr. 63:1985;1180-1186.
86. Schwartzkopff B., Schilling G., Simon H. Comparison of tocainide and prajmalium bitartrate for the treatment of ventricular arrhythmias. Arzneimittelforschung. 33:1983;153-158.
87. Mörike K., Hardtmann E., Heimburg P., Eichelbaum M. The impact of polymorphic N-propylajmaline metabolism on dose requirement and antiarrhythmic efficacy of the drug. Eur. J. Pharmacol. (abstract). 183:1990;628-629.
88. Silas J.H., Lennard M.S., Tucker G.T., Smith A.J., Malcolm S.L., Marten T.R. Why hypertensive patients vary in their response to oral debrisoquine. Br. Med. J. 1:1977;422-425.
89. Idle J.R., Mahgoub A., Lancaster R., Smith R.L. Hypotensive response to debrisoquine and hydroxylation phenotype. Life Sci. 22:1978;979-983.
90. J.R. Idle, R.L. Smith, The debrisoquine hydroxylation gene: a gene of multiple consequence, in: L. Lemberger, M.M. Reidenberg (Eds.), Proceedings of the Second World Conference on Clinical Pharmacology and Therapeutics. American Society for Pharmacology and Experimental Therapeutics, Baltimore, 1984, pp. 148-164.
91. Pierce D.M., Abrams S.M., Franklin R.A. Pharmacokinetics and systemic availability of the antihypertensive agent indoramin and its metabolite 6-hydroxyindoramin in healthy subjects. Eur. J. Clin. Pharmacol. 32:1987;619-623.
92. Shah R.R., Oates N.S., Idle J.R., Smith R.L., Lockhart J.D. Impaired oxidation of debrisoquine in patients with perhexiline neuropathy. Br. Med. J. Clin. Res. 284:1982;295-299.
93. Shah R.R., Oates N.S., Idle J.R., Smith R.L., Lockhart J.D. Prediction of subclinical perhexiline neuropathy in a patient with inborn error of debrisoquine hydroxylation. Am. Heart J. 105:1983;159-161.
94. Alvan G., Balant L.P., Bechtel P.R., Boobis A.R., Gram L.F., Pithan K. European Consensus Conference on Pharmacogenetics, Brussels, Belgium. Commission of the European Communities. 28:1990;167.
95. Bertilsson L., Dahl M.L. Polymorphic drug oxidation: Relevance to the treatment of psychiatric disorders. CNS Drugs. 5:1996;200-223.
96. Pollock B.G., Mulsant B.H., Sweet R.A., Rosen J., Perel J.M. Pharmacogenetics of neuroleptics in the elderly. Neuropsychopharmacology. 3S:1994;918S.
97. Meyer U.A., Amrein R., Balant L.P., Bertilsson L., Eichelbaum M., Guentert T.W., Henauer S., Jackson P., Laux G., Mikkelsen H., Peck C., Pollock B.G., Priest R., Sjöqvist F., Delini-Stula A. Antidepressants and drug-metabolizing enzymes - Expert group report. Acta Psychiatr. Scand. 93:1996;71-79.
98. Tacke U., Leinonen E., Lillsunde P., Seppala T., Arvela P., Pelkonen O., Ylitalo P. Debrisoquine hydroxylation phenotypes of patients with high versus low to normal serum antidepressant concentrations. J. Clin. Psychopharmacol. 12:1992;262-267.
99. F. Sjöqvist, W. Hammer, C.M. Ideström, M. Lind, D. Tuck, M. Asberg, Plasma levels of monomethylated tricyclic antidepressants and side-effects in man, in: Proceedings of the European Society for the Study of Drug Toxicity. Volume IX, Toxicity and Side-Effects of Psychotropic Drugs. Excerpta Medica International Congress Series No. 145, 1967, pp. 246-257.
100. Dahl M.L., Bertilsson L. Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenetics. 3:1993;61-70.
101. Mellström B., Bertilsson L., Traskman L., Rollins D., Asberg M., Sjöqvist F. Intraindividual similarity in the metabolism of amitriptyline and chlorimipramine in depressed patients. Pharmacology. 19:1979;282-287.
102. Balant-Gorgia A.E., Balant L.P., Genet C., Dayer P., Aeschlimann J.M., Garrone G. Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolites. Eur. J. Clin. Pharmacol. 31:1986;449-455.
103. Spina E., Birgersson C., von Bahr C., Ericsson O., Mellström B., Steiner E., Sjöqvist F. Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes. Clin. Pharmacol. Ther. 36:1984;677-682.
104. Spina E., Steiner E., Ericsson O., Sjöqvist F. Hydroxylation of desmethylimipramine: dependence on the debrisoquine hydroxylation phenotype. Clin. Pharmacol. Ther. 41:1987;314-319.
105. Dahl M.L., Iselius L., Alm C., Svensson J.O., Lee D., Johansson I., Ingelman-Sundberg M., Sjöqvist F. Polymorphic 2-hydroxylation of desipramine: A population and family study. Eur. J. Clin. Pharmacol. 44:1993;445-450.
106. Bertilsson L., Aberg-Wistedt A. The debrisoquine hydroxylation test predicts steady-state plasma levels of desipramine. Br. J. Clin. Pharmacol. 15:1983;388-390.
107. Brøsen K., Gram L.F. First-pass metabolism of imipramine and desipramine: impact of the sparteine oxidation phenotype. Clin. Pharmacol. Ther. 43:1988;400-406.
108. Bluhm R.E., Wilkinson G.R., Shelton R., Branch R.A. Genetically determined drug-metabolizing activity and desipramine-associated cardiotoxicity: A case report. Clin. Pharmacol. Ther. 53:1993;89-95.
109. Mellström B., Bertilsson L., Säwe J., Schulz H.U., Sjöqvist F. E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation. Clin. Pharmacol. Ther. 30:1981;189-193.
110. Nordin C., Siwers B., Benitez J., Bertilsson L. Plasma concentrations of nortriptyline and its 10-hydroxy metabolite in depressed patients - relationship to the debrisoquine hydroxylation metabolic ratio. Br. J. Clin. Pharmacol. 19:1985;832-835.
111. Gram L.F., Brøsen K., Kragh-Sorensen P., Christensen P. Steady-state plasma levels of E- and Z-10-OH-nortriptyline in nortriptyline-treated patients: significance of concurrent medication and the sparteine oxidation phenotype. Ther. Drug Monit. 11:1989;508-514.
112. Nielsen K.K., Brøsen K., Hansen M.G.J., Gram L.F. Single-dose kinetics of clomipramine: Relationship to the sparteine and S-mephenytoin oxidation polymorphisms. Clin. Pharmacol. Ther. 55:1994;518-527.
113. Firkusny L., Gleiter C.H. Maprotiline metabolism appears to co-segregate with the genetically-determined CYP2D6 polymorphic hydroxylation of debrisoquine. Br. J. Clin. Pharmacol. 37:1994;383-388.
114. Dahl M.L., Tybring G., Elwin C.E., Alm C., Andreasson K., Gyllenpalm M., Bertilsson L. Stereoselective disposition of mianserin is related to debrisoquine hydroxylation polymorphism. Clin. Pharmacol. Ther. 56:1994;176-183.
115. Koyama E., Chiba K., Tani M., Ishizaki T. Identification of human cytochrome P450 isoforms involved in the stereoselective metabolism of mianserin enantiomers. J. Pharmacol. Exp. Ther. 278:1996;21-30.
116. Sindrup S.H., Brøsen K., Gram L.F., Hallas J., Skjelbo E., Allen A., Allen G.D., Cooper S.M., Mellows G., Tasker T.C.G., Zussman B.D. The relationship between paroxetine and the sparteine oxidation polymorphism. Clin. Pharmacol. Ther. 51:1992;278-287.
117. Bloomer J.C., Woods F.R., Haddock R.E., Lennard M.S., Tucker G.T. The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes. Br. J. Clin. Pharmacol. 33:1992;521-523.
118. Carrillo J.A., Dahl M.L., Svensson J.O., Alm C., Rodriguez I., Bertilsson L. Disposition of fluvoxamine in human is determined by the polymorphic CYP2D6 and also by the CYP1A2 activity. Clin. Pharmacol. Ther. 60:1996;183-190.
119. Otton S.V., Ball S.E., Cheung S.W., Inaba T., Rudolph R.L., Sellers E.M. Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br. J. Clin. Pharmacol. 41:1996;149-156.
120. Otton S.V., Inaba T., Kalow W. Inhibition of sparteine oxidation in human liver by tricyclic antidepressants and other drugs. Life Sci. 32:1983;795-800.
121. Inaba T., Nakano M., Otton S.V., Mahon W.A., Kalow W. A human cytochrome P-450 characterized by inhibition studies as the sparteine-debrisoquine monooxygenase. Can. J. Physiol. Pharmacol. 62:1984;860-862.
122. von Bahr C., Movin G., Nordin C., Liden A., Hammarlund-Udenaes M., Hedberg A., Ring H., Sjöqvist F. Plasma levels of thioridazine and metabolites are influenced by the debrisoquine hydroxylation phenotype. Clin. Pharmacol. Ther. 49:1991;234-240.
123. Dahl-Puustinen M.L., Liden A., Alm C., Nordin C., Bertilsson L. Disposition of perphenazine is related to polymorphic debrisoquine hydroxylation in human beings. Clin. Pharmacol. Ther. 46:1989;78-81.
124. Jerling M., Dahl M.L., Aberg-Wistedt A., Liljenberg B., Landell N.E., Bertilsson L., Sjöqvist F. The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol. Clin. Pharmacol. Ther. 59:1996;423-428.
125. Linnet K., Wiborg O. Steady-state serum concentrations of the neuroleptic perphenazine in relation to CYP2D6 genetic polymorphism. Clin. Pharmacol. Ther. 60:1996;41-47.
126. Huang M.L., Van Peer A., Woestenborghs R., De Coster R., Heykants J., Jansen A.A.I., Zylicz Z., Visscher H.W., Jonkman J.H.G. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin. Pharmacol. Ther. 54:1993;257-268.
127. Llerena A., Alm C., Dahl M.L., Ekqvist B., Bertilsson L. Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype. Ther. Drug Monit. 14:1992;92-97.
128. Nyberg S., Farde L., Halldin C., Dahl M.L., Bertilsson L. D-2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate. Am. J. Psychiatry. 152:1995;173-178.
129. Young D., Midha K.K., Fossler M.J., Hawes E.M., Hubbard J.W., McKay G., Korchinski E.D. Effect of quinidine on the interconversion kinetics between haloperidol and reduced haloperidol in humans: Implications for the involvement of cytochrome P450IID6. Eur. J. Clin. Pharmacol. 44:1993;433-438.
130. Tyndale R.F., Kalow W., Inaba T. Oxidation of reduced haloperidol to haloperidol: involvement of human P450IID6 (sparteine/debrisoquine monooxygenase). Br. J. Clin. Pharmacol. 31:1991;655-660.
131. Dayer P., Desmeules J., Leemann T., Striberni R. Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI). Biochem. Biophys. Res. Commun. 152:1988;411-416.
132. Chen Z.R., Somogyi A.A., Bochner F. Polymorphic O-demethylation of codeine. Lancet. 2:1988;914-915.
133. Yue Q.Y., Svensson J.O., Alm C., Sjöqvist F., Säwe J. Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. Br. J. Clin. Pharmacol. 28:1989;639-645.
134. Chen Z.R., Somogyi A.A., Reynolds G., Bochner F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br. J. Clin. Pharmacol. 31:1991;381-390.
135. Sindrup S.H., Brøsen K. The pharmacogenetics of codeine hypoalgesia. Pharmacogenetics. 5:1995;335-346.
136. Sindrup S.H., Brøsen K., Bjerring P., Arendt-Nielsen L., Larsen U., Angelo H.R., Gram L.F. Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin. Pharmacol. Ther. 48:1990;686-693.
137. Desmeules J., Gascon M.P., Dayer P., Magistris M. Impact of environmental and genetic factors on codeine analgesia. Eur. J. Clin. Pharmacol. 41:1991;23-26.
138. Caraco Y., Sheller J., Wood A.J.J. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J. Pharmacol. Exp. Ther. 278:1996;1165-1174.
139. Persson K., Sjöström S., Sigurdardottir I., Molnar V., Hammarlund-Udenaes M., Rane A. Patient-controlled analgesia (PCA) with codeine for postoperative pain relief in ten extensive metabolisers and one poor metaboliser of dextromethorphan. Br. J. Clin. Pharmacol. 39:1995;182-186.
140. Capon D.A., Bochner F., Kerry N., Mikus G., Danz C., Somogyi A.A. The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans. Clin. Pharmacol. Ther. 60:1996;295-307.
141. Fischer V., Vickers A.E.M., Heitz F., Mahadevan S., Baldeck J.P., Minery P., Tynes R. The polymorphic cytochrome P-4502D6 is involved in the metabolism of both 5-hydroxytryptamine antagonists, tropisetron and ondansetron. Drug Metab. Dispos. 22:1994;269-274.
142. Firkusny L., Kroemer H.K., Eichelbaum M. In vitro characterization of cytochrome P450 catalysed metabolism of the antiemetic tropisetron. Biochem. Pharmacol. 49:1995;1777-1784.
143. Sanwald P., David M., Dow J. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron: Comparison with other indole-containing 5-HT-3 antagonists. Drug Metab. Dispos. 24:1996;602-609.
144. De Bruijn K.M. Tropisetron. A review of the clinical experience. Drugs. 43(Suppl. 3):1992;11-22.
145. Pritchard J.F. Ondansetron metabolism and pharmacokinetics. Semin. Oncol. 19(Suppl. 10):1992;9-15.
146. Ashforth E.I.L., Palmer J.L., Bye A., Bedding A. The pharmacokinetics of ondansetron after intravenous injection in healthy volunteers phenotyped as poor or extensive metabolisers of debrisoquine. Br. J. Clin. Pharmacol. 37:1994;389-391.
147. Huebert N.D., Schwartz J.J., Hinze C., Haegele K.D. Bioavailability and the effect of food on the pharmacokinetics of dolasetron mesylate and its active metabolite, MDL 74156, in man. Br. J. Clin. Pharmacol. 37:1993;120P-121P.
148. Tucker G.T., Lennard M.S., Ellis S.W., Woods H.F., Cho A.K., Lin L.Y., Hiratsuka A., Schmitz D.A., Chu T.Y.Y. The demethylenation of methylenedioxymethamphetamine ("ecstasy") by debrisoquine hydroxylase (CYP2D6). Biochem. Pharmacol. 47:1994;1151-1156.
149. Kalow W. Pharmacogenetic variability in brain and muscle. J. Pharm. Pharmacol. 46(Suppl. 1):1994;425-432.
150. Hori R., Okumura K., Inui K., Yasuhara M., Yamada K., Sakurai T., Kawai C. Quinidine-induced rise in ajmaline plasma concentration. J. Pharm. Pharmacol. 36:1984;202-204.
151. Funck-Brentano C., Turgeon J., Woosley R.L., Roden D.M. Effect of low dose quinidine on encainide pharmacokinetics and pharmacodynamics. Influence of genetic polymorphism. J. Pharmacol. Exp. Ther. 249:1989;134-142.
152. Harvey A.T., Preskorn S.H. Cytochrome P450 enzymes: Interpretation of their interactions with selective serotonin reuptake. J. Clin. Psychopharmacol. 16:1996;273-285.
153. Brøsen K. Are pharmacokinetic drug interactions with the SSRIs an issue? Int. Clin. Psychopharmacol. 11(Suppl. 1):1996;23-27.
154. Brøsen K. The pharmacogenetics of the selective serotonin reuptake inhibitors. Clin. Invest. 71:1993;1002-1009.
155. Vaughan D.A. Interaction of fluoxetine with tricyclic antidepressants. Am. J. Psychiatry. 145:1988;1478.
156. Küpfer A., Desmond P., Patwardhan R., Schenker S., Branch R.A. Mephenytoin hydroxylation deficiency: kinetics after repeated doses. Clin. Pharmacol. Ther. 35:1984;33-39.
157. G.R. Wilkinson, F.P. Guengerich, R.A. Branch, Genetic polymorphism of S-mephenytoin hydroxylation, in: W. Kalow (Ed.), Pharmacogenetics of drug metabolism, Pergamon, New York, 1992, pp. 657-685.
158. Küpfer A., Preisig R. Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur. J. Clin. Pharmacol. 26:1984;753-759.
159. Jacqz E., Hall S.D., Branch R.A., Wilkinson G.R. Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a co-regulated substrate, mephobarbital. Clin. Pharmacol. Ther. 39:1986;646-653.
160. Goldstein J.A., Faletto M.B., Romkes-Sparks M., Sullivan T., Kitareewan S., Raucy J.L., Lasker J.M., Ghanayem B.I. Evidence that CYP2C19 is the major (S)-mephenytoin 4′-hydroxylase in humans. Biochemistry. 33:1994;1743-1752.
161. Daly A.K. Molecular basis of polymorphic drug metabolism. J. Mol. Med. 73:1995;539-553.
162. Goldstein J.A., De Morais S.M.F. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics. 4:1994;285-299.
163. Inaba T., Nebert D.W., Burchell B., Watkins P.B., Goldstein J.A., Bertilsson L., Tucker G.T. Pharmacogenetics in clinical pharmacology and toxicology. Can. J. Physiol. Pharmacol. 73:1995;331-338.
164. Romkes M., Faletto M.B., Blaisdell J.A., Raucy J.L., Goldstein J.A. Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily. Biochemistry. 30:1991;3247-3255.
165. Wrighton S.A., Stevens J.C., Becker G.W., Van den Branden M. Isolation and characterization of human liver cytochrome P450 2C19: Correlation between 2C19 and S-mephenytoin 4′-hydroxylation. Arch. Biochem. Biophys. 306:1993;240-245.
166. De Morais S.M.F., Wilkinson G.R., Blaisdell J., Nakamura K., Meyer U.A., Goldstein J.A. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J. Biol. Chem. 269:1994;15419-15422.
167. De Morais S.M.F., Wilkinson G.R., Blaisdell J., Meyer U.A., Nakamura K., Goldstein J.A. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol. Pharmacol. 46:1994;594-598.
168. Brøsen K., De Morais S.M.F., Meyer U.A., Goldstein J.A. A multifamily study on the relationship between CYP2C19 genotype and S-mephenytoin oxidation phenotype. Pharmacogenetics. 5:1995;312-317.
169. Yasumori T., Nagata K., Yang S.K., Chen L.S., Murayama N., Yamazoe Y., Kato R. Cytochrome P450 mediated metabolism of diazepam in human and rat: Involvement of human CYP2C in N-demethylation in the substrate concentration-dependent manner. Pharmacogenetics. 3:1993;291-301.
170. Yasumori T., Qing-Hua L., Yamazoe Y., Ueda M., Tsuzuki T., Kato R. Lack of low K(m) diazepam N-demethylase in livers of poor metabolizers for S-mephenytoin 4′-hydroxylation. Pharmacogenetics. 4:1994;323-331.
171. Andersson T., Miners J.O., Veronese M., Birkett D.J. Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br. J. Clin. Pharmacol. 38:1994;131-137.
172. Wedlund P.J., Aslanian W.S., Jacqz E., McAllister C.B., Branch R.A., Wilkinson G.R. Phenotypic differences in mephenytoin pharmacokinetics in normal subjects. J. Pharmacol. Exp. Ther. 234:1985;662-669.
173. Nakamura K., Goto F., Ray W.A., McAllister C.B., Jacqz E., Wilkinson G.R., Branch R.A. Interethnic differences in genetic polymorphism of debrisoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin. Pharmacol. Ther. 38:1985;402-408.
174. Bertilsson L., Henthorn T.K., Sanz E., Tybring G., Säwe J., Villen T. Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquine, hydroxylation phenotype. Clin. Pharmacol. Ther. 45:1989;348-355.
175. Zhang Y.A., Reviriego J., Lou Y.Q., Sjöqvist F., Bertilsson L. Diazepam metabolism in native Chinese poor and extensive hydroxylators of S-mephenytoin: interethnic differences in comparison with white subjects. Clin. Pharmacol. Ther. 48:1990;496-502.
176. Skjelbo E., Brøsen K., Hallas J., Gram L.F. The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin. Pharmacol. Ther. 49:1991;18-23.
177. Chiba K., Saitoh A., Koyama E., Tani M., Hayashi M., Ishizaki T. The role of S-mephenytoin 4′-hydroxylase in imipramine metabolism by human liver microsomes: A two-enzyme kinetic analysis of N-demethylation and 2-hydroxylation. Br. J. Clin. Pharmacol. 37:1994;237-242.
178. Koyama E., Sohn D.R., Shin S.G., Chiba K., Shin J.G., Kim Y.H., Echizen H., Ishizaki T. Metabolic disposition of imipramine in oriental subjects: Relation to metoprolol alpha-hydroxylation and S-mephenytoin 4′-hydroxylation phenotypes. J. Pharmacol. Exp. Ther. 271:1994;860-867.
179. Koyama E., Tanaka T., Chiba K., Kawakatsu S., Morinobu S., Totsuka S., Ishizaki T. Steady-state plasma concentrations of imipramine and desipramine in relation to S-mephenytoin 4′-hydroxylation status Japanese depressive patients. J. Clin. Psychopharmacol. 16:1996;286-293.
180. Lemoine A., Gautier J.C., Azoulay D., Kiffel L., Belloc C., Guengerich F.P., Maurel P., Beaune P., Leroux J.P. Major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver. Mol. Pharmacol. 43:1993;827-832.
181. Breyer-Pfaff U., Pfandl B., Nill K., Nusser E., Monney C., Jonzier-Perey M., Baettig D., Baumann P. Enantioselective amitriptyline metabolism in patients phenotyped for two cytochrome P450 isozymes. Clin. Pharmacol. Ther. 52:1992;350-358.
182. Sindrup S.H., Brøsen K., Hansen M.G.J., Aaes-Jørgensen T., Overø K.F., Gram L.F. Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther. Drug Monit. 15:1993;11-17.
183. Gram L.F., Guentert T.W., Grange S., Vistisen K., Brøsen K. Moclobemide, a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and CYP1A2: A panel study. Clin. Pharmacol. Ther. 57:1995;670-677.
184. Adedoyin A., Prakash C., O'Shea D., Blair I.A., Wilkinson G.R. Stereoselective disposition of hexobarbital and its metabolites: Relationship to the S-mephenytoin polymorphism in Caucasian and Chinese subjects. Pharmacogenetics. 4:1994;27-38.
185. Knodell R.G., Dubey R.K., Wilkinson G.R., Guengerich F.P. Oxidative metabolism of hexobarbital in human liver: relationship to polymorphic S-mephenytoin 4-hydroxylation. J. Pharmacol. Exp. Ther. 245:1988;845-849.
186. Küpfer A., Branch R.A. Stereoselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation. Clin. Pharmacol. Ther. 38:1985;414-418.
187. Zhou H.H., Anthony L.B., Wood A.J., Wilkinson G.R. Induction of polymorphic 4′-hydroxylation of S-mephenytoin by rifampicin. Br. J. Clin. Pharmacol. 30:1990;471-475.
188. Arns P.A., Wilkinson G.R., Branch R.A. The stereoselective disposition of mephenytoin provides a probe of hepatic function and development of portasystemic shunts in liver disease. Hepatology. 8:1988;1277.
189. Flockhart D.A. Drug interactions and the cytochrome P450 system. The role of cytochrome P450 2C19. Clin. Pharmacokinet. 29(Suppl. 1):1995;45-52.
190. Jeppesen U., Gram L.F., Vistisen K., Loft S., Poulsen H.E., Brøsen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur. J. Clin. Pharmacol. 51:1996;73-78.
191. Alvan G., von Bahr C., Seidemann P., Sjöqvist F. High plasma concentrations of beta-receptor blocking drugs and deficient debrisoquine hydroxylation. Lancet. 1:1982;333.
192. Alvan G., Grind M., Graffner C., Sjöqvist F. Relationship of N-demethylation of amiflamine and its metabolite to debrisoquine hydroxylation polymorphism. Clin. Pharmacol. Ther. 36:1984;515-519.
193. Balant-Gorgia A.E., Schulz P., Dayer P., Balant L., Kubli A., Gertsch C., Garrone G. Role of oxidation polymorphism on blood and urine concentrations of amitriptyline and its metabolites in man. Arch. Psychiatr. Nervenkr. 232:1982;215-222.
194. Ebner T., Eichelbaum M. The metabolism of aprindine in relation to the sparteine/debrisoquine polymorphism. Br. J. Clin. Pharmacol. 35:1993;426-430.
195. Jedrychowski M., Feifel N., Bieck P.R., Schmidt K. Metabolism of the new MAO-A inhibitor brofaromine in poor and extensive metabolizers of debrisoquine. J. Pharm. Biomed. Anal. 11:1993;251-255.
196. Dayer P., Leemann T., Küpfer A., Kronbach T., Meyer U.A. Stereo- and regioselectivity of hepatic oxidation in man - effect of the debrisoquine/sparteine phenotype on bufuralol hydroxylation. Eur. J. Clin. Pharmacol. 31:1986;313-318.
197. Narimatsu S., Masubuchi Y., Hosokawa S., Ohmori S., Kitada M., Suzuki T. Involvement of a cytochrome P4502D subfamily in human liver microsomal bunitrolol 4-hydroxylation. Biol. Pharm. Bull. 17:1994;803-807.
198. Pressacco J., Muller R., Kalow W. Interactions of bupranolol with the polymorphic debrisoquine/sparteine monooxygenase (CYP2D6). Eur. J. Clin. Pharmacol. 45:1993;261-264.
199. Narimatsu S., Kariya S., Isozaki S., Ohmori S., Kitada M., Hosokawa S., Masubuchi Y., Suzuki T. Involvement of CYP2D6 in oxidative metabolism of cinnarizine and flunarizine in human liver microsomes. Biochem. Biophys. Res. Commun. 193:1993;1262-1268.
200. Gross A.S., Phillips A.C., Rieutord A., Shenfield G.M. The influence of the sparteine/debrisoquine genetic polymorphism on the disposition of dexfenfluramine. Br. J. Clin. Pharmacol. 41:1996;311-317.
201. Küpfer A., Schmid B., Preisig R., Pfaff G. Dextromethorphan as a safe probe for debrisoquine hydroxylation polymorphism. Lancet. 2:1984;517-518.
202. Fromm M.F., Hofmann U., Griese E.-U., Mikus G. Dihydrocodeine: A new opioid substrate for the polymorphic CYP2D6 in humans. Clin. Pharmacol. Ther. 58:1995;374-382.
203. Rane A., Modiri A.R., Gerdin E. Ethylmorphine O-deethylation cosegregates with the debrisoquine genetic metabolic polymorphism. Clin. Pharmacol. Ther. 52:1992;257-264.
204. Beckmann J., Hertrampf R., Gundert-Remy U., Mikus G., Gross A.S., Eichelbaum M. Is there a genetic factor in flecainide toxicity? Br. Med. J. 297:1988;1316.
205. Sloan T.P., Mahgoub A., Lancaster R., Idle J.R., Smith R.L. Polymorphism of carbon oxidation of drugs and clinical implications. Br. Med. J. 2:1978;655-657.
206. Otton S.V., Schadel M., Cheung S.W., Kaplan H.L., Busto U.E., Sellers E.M. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin. Pharmacol. Ther. 54:1993;463-472.
207. Kitchen I., Tremblay J., Andre J., Dring L.G., Idle J.R., Smith R.L., Williams R.T. Interindividual and interspecies variation in the metabolism of the hallucinogen 4-methoxyamphetamine. Xenobiotica. 9:1979;397-404.
208. Roy S.D., Hawes E.M., McKay G., Korchinski E.D., Midha K.K. Metabolism of methoxyphenamine in extensive and poor metabolizers of debrisoquine. Clin. Pharmacol. Ther. 38:1985;128-133.
209. Davi H., Bonnet J.M., Berger Y. Disposition of minaprine in animals and in human extensive and limited debrisoquine hydroxylators. Xenobiotica. 22:1992;171-184.
210. Mikus G., Somogyi A.A., Bochner F., Eichelbaum M. Cytochrome P-450 IID6 is involved in two O-demethylation reactions of codeine metabolism. Clin. Exp. Pharm. Physiol. Suppl. 17:1990;53.
211. Cooper R.G., Evans D.A., Whibley E.J. Polymorphic hydroxylation of perhexiline maleate in man. J. Med. Genet. 21:1984;27-33.
212. Oates N.S., Shah R.R., Idle J.R., Smith R.L. Genetic polymorphism of phenformin 4-hydroxylation. Clin. Pharmacol. Ther. 32:1982;81-89.
213. 1 antagonist promethazine in human liver microsomes. Pharmacogenetics. 6:1996;449-457.
214. Feher M.D., Lucas R.A., Farid N.A., Idle J.R., Bergstrom R.F., Lemberger L., Sever P.S. Single dose pharmacokinetics of tomoxetine in poor and extensive metabolisers of debrisoquine. Br. J. Clin. Pharmacol. 26:1988;231P.
215. Dahl M.L., Ekqvist B., Widen J., Bertilsson L. Disposition of the neuroleptic zuclopenthixol cosegregates with the polymorphic hydroxylation of debrisoquine in humans. Acta Psychiatr. Scand. 84:1991;99-102.
216. Panserat S., Mura C., Gerard N., Vincent-Viry M., Galteau M.M., Jacqz-Aigrain E., Krishnamoorthy R. DNA haplotype-dependent differences in the amino acid sequence of debrisoquine 4-hydroxylase (CYP2D6): Evidence for two major allozymes in extensive metabolisers. Hum. Genet. 94:1994;401-406.
217. M. Ingelman-Sundberg, M. Oscarson, I. Persson, C.M. Masimirembwa, M.L. Dahl, L. Bertilsson, F. Sjöqvist, I. Johansson, Genetic polymorphism of human drug metabolizing enzymes. Recent aspects on polymorphic forms of cytochromes P450, in: G. Alvan, L.P. Balant, P.R. Bechtel, A.R. Boobis, L.F. Gram, G. Paintaud, K. Pithan (Eds.), European conference on specificity and variability in drug metabolism. EU, Luxembourg, 1995, pp. 93-110.
218. Kagimoto M., Heim M., Kagimoto K., Zeugin T., Meyer U.A. 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. 265:1990;17209-17214.
219. Gough A.C., Miles J.S., Spurr N.K., Moss J.E., Gaedigk A., Eichelbaum M., Wolf C.R. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature. 347:1990;773-776.
220. Hanioka N., Kimura S., Meyer U.A., Gonzalez F.J. The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934-A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3′ splice recognition site. Am. J. Hum. Genet. 47:1990;994-1001.
221. Gaedigk A., Blum M., Gaedigk R., Eichelbaum M., Meyer U.A. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am. J. Hum. Genet. 48:1991;943-950.
222. Steen V.M., Molven A., Aarskog N.K., Gulbrandsen A.K. Homologous unequal cross-over involving a 2.8 kb direct repeat as a mechanism for the generation of allelic variants of the human cytochrome P450 CYP2D6 gene. Hum. Mol. Genet. 4:1995;2251-2257.
223. Saxena R., Shaw G.L., Relling M.V., Frame J.N., Moir D.T., Evans W.E., Caporaso N., Weiffenbach B. Identification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotype. Hum. Mol. Genet. 3:1994;923-926.
224. Evert B., Griese E.-U., Eichelbaum M. Cloning and sequencing of a new non-functional CYP2D6 allele: Deletion of T-1795 in exon 3 generates a premature stop codon. Pharmacogenetics. 4:1994;271-274.
225. Daly A.K., Leathart J.B., London S.J., Idle J.R. An inactive cytochrome P450 CYP2D6 allele containing a deletion and a base substitution. Hum. Genet. 95:1995;337-341.
226. Evert B., Griese E.-U., Eichelbaum M. A missense mutation in exon 6 of the CYP2D6 gene leading to a histidine 324 to proline exchange is associated with the poor metabolizer phenotype of sparteine. Naunyn-Schmiedeberg's Arch. Pharmacol. 350:1994;434-439.
227. Broly F., Marez D., Sabbagh N., Legrand M., Millecamps S., Lo-Guidice J.M., Boone P., Meyer U.A. An efficient strategy for detection of known and new mutations of the CYP2D6 gene using single strand conformation polymorphism analysis. Pharmacogenetics. 5:1995;373-384.
228. Marez D., Sabbagh N., Legrand M., Lo-Guidice J.M., Boone P., Broly F. A novel CYP2D6 allele with an abolished splice recognition site associated with the poor metabolizer phenotype. Pharmacogenetics. 5:1995;305-311.
229. Marez D., Legrand M., Sabbagh N., Lo-Guidice J.M., Boone P., Broly F. An additional allelic variant of the CYP2D6 gene causing impaired metabolism of sparteine. Hum. Genet. 97:1996;668-670.
230. Panserat S., Mura C., Gerard N., Vincent-Viry M., Galteau M.M., Jacqz-Aigrain E., Krishnamoorthy R. An unequal cross-over event within the CYP2D gene cluster generates a chimeric CYP2D7/CYP2D6 gene which is associated with the poor metabolizer phenotype. Br. J. Clin. Pharmacol. 40:1995;361-367.
231. S. Wang, Phenotypes and genotypes of debrisoquine hydroxylation polymorphism in Chinese. Master's thesis, National Cheng Kung University, Tainan, Taiwan, 1992.
232. Sachse C., Brockmöller J., Bauer S., Reum T., Roots I. A rare insertion of T-226 in exon 1 of CYP2D6 causes a frameshift and is associated with the poor metabolizer phenotype: CYP2D6*15. Pharmacogenetics. 6:1996;269-272.
233. Daly A.K., Fairbrother K.S., Andreassen O.A., London S.J., Idle J.R., Steen V.M. Characterization and PCR-based detection of two different hybrid CYP2D7P/CYP2D6 alleles associated with the poor metabolizer phenotype. Pharmacogenetics. 6:1996;319-328.
234. Yokoi T., Kosaka Y., Chida M., Chiba K., Nakamura H., Ishizaki T., Kinoshita M., Sato K., Gonzalez F.J., Kamataki T. A new CYP2D6 allele with a nine base insertion in exon 9 in a Japanese population associated with poor metabolizer phenotype. Pharmacogenetics. 6:1996;395-401.
235. Tyndale R., Aoyama T., Broly F., Matsunaga T., Inaba T., Kalow W., Gelboin H.V., Meyer U.A., Gonzalez F.J. Identification of a new CYP2D6 allele lacking the codon encoding Lys-281: possible association with the poor metabolizer phenotype. Pharmacogenetics. 1:1991;26-32.
236. Broly F., Meyer U.A. Debrisoquine oxidation polymorphism: phenotypic consequences of a 3-base-pair deletion in exon 5 of the CYP2D6 gene. Pharmacogenetics. 3:1993;123-130.
237. Olsen H., Koppang E., Alvan G., Morland J. Carisoprodol elimination in humans. Ther. Drug Monit. 16:1994;337-340.
238. Andersson T., Lagerström P.O., Unge P. A study of the interaction between omeprazole and phenytoin in epileptic patients. Ther. Drug Monit. 12:1990;329-333.
239. Ward S.A., Helsby N.A., Skjelbo E., Brøsen K., Gram L.F., Breckenridge A.M. The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism - a panel study. Br. J. Clin. Pharmacol. 31:1991;689-692.