Skip to main content
SpringerLink
Log in

Clinical Relevance of Pharmacogenetics

  • Chapter
Pharmacokinetics of Drugs

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 110))

  • 348 Accesses

Abstract

One of the central problems in pharmacotherapy is the interindividual variability in response to drugs. While in vitro experiments show a close relationship between dose and resulting effects, large differences are observed once the same dose is administered to a population of patients.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Alvan G, von Bahr C, Seideman P, Sjöqvist F (1982) High plasma concentrations of β-receptor blocking drugs and deficient debrisoquine hydroxylation. Lancet 1: 333

    PubMed  CAS  Google Scholar 

  • Alvan G, Grind M, Graffner C, Sjöqvist F (1984) Relationship of N-demethylation of amiflamine and its metabolite to debrisoquine hydroxylation polymorphism. Clin Pharmacol Ther 36: 515–519

    PubMed  CAS  Google Scholar 

  • Anders HH, Weber WW (1986) N-acetylation pharmacogenetics: Michealis-Menten constants for aryamine drugs as predictors of their N-acetylation rates in vivo. Drug Metab Dispos 14: 382–385

    Google Scholar 

  • Andersson T, Regardh CG, Dahl-Puustinen ML, Bertilsson L (1990) Slow omeprazole metabolizers are also poor S-mephenytoin hydroxylators. Ther Drug Monit 12: 415–416

    PubMed  CAS  Google Scholar 

  • Arns PA, Wilkinson GR, Branch RA (1988) The stereoselective disposition of mephenytoin provides a probe of hepatic function and development of portasystemic shunts in liver disease. Hepatology 8: 1277

    Google Scholar 

  • Ayesh R, Smith RL (1992) Genetic polymorphism of trimethylamine N-oxidation. In: Kalow W (ed) Pharmacogenetics of drug metabolism. Pergamon, New York, pp 315–333

    Google Scholar 

  • 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: 449–455

    PubMed  CAS  Google Scholar 

  • 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: 1326

    Google Scholar 

  • Bertilsson L, Mellström B, Sjöqvist F, Martensson B, Asberg M (1981) Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implications. Lancet 1: 560–561

    PubMed  CAS  Google Scholar 

  • Bertilsson L, Henthorn TK, Sanze E, Tybring G, Säwe J, Villen T (1989) Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquine hydroxylation phenotype. Clin Pharmacol Ther 45: 348–355

    PubMed  CAS  Google Scholar 

  • Blum M, Grant DM, McBride W, Heim M, Meyer UA (1990) Human arylamine N-acetyltransferase genes: isolation, chromosomal localisation and functional expression. DNA Cell Biol 9: 193–203

    PubMed  CAS  Google Scholar 

  • Blum M, Demierre A, Grant DM, Heim M, Meyer UA (1991) Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc Natl Acad Sci USA 88: 5237–5241

    PubMed  CAS  Google Scholar 

  • Bönike R, Reif W (1953) Enzymatische Inaktivierung von Isonicotinsaurehydrazid im menschlichen und tierischen Organismus. Arch Exp Pathol Pharmakol 220: 321–333

    Google Scholar 

  • Botsch S, Gautier JC, Beaune P, Eichelbaum M, Kroemer HK (1993) Identification and characterization of the cytochrome P450 enzymes involved in N-dealkylation of propafenone: molecular base for interaction potential and variable disposition of active metabolites. Mol Pharmacol 43: 120–126

    PubMed  CAS  Google Scholar 

  • Brian WR, Srivastava PK, Umbenhauer DR, Lloyd RS, Guengerich FP (1989) Expression of a human liver cytochrome P-450 protein with tolbutamide hydroxylase activity in Saccharomyces cerevisiae. Biochemistry 28: 4993–4999

    PubMed  CAS  Google Scholar 

  • Broly F, Gaedigk A, Heim M, Eichelbaum M, Mörike K, Meyer UA (1991) Debrisoquine/sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population. DNA Cell Biol 10: 545 - 558

    PubMed  CAS  Google Scholar 

  • Brosen K, Gram LF (1988) First-pass metabolism of imipramine and desipramine: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 43: 400–406

    PubMed  CAS  Google Scholar 

  • Brosen K, Gram LF, Klysner R, Bech P (1986) Steady-state levels of imipramine and its metabolites: significance of dose-dependent kinetics. Eur J Clin Pharmacol 30: 43–49

    PubMed  CAS  Google Scholar 

  • Brosen K, Gram LF, Haghfelt T, Bertilsson L (1987) Extensive metabolizers of debrisoquine become poor metabolizers during quinidine treatment: Pharmacol Toxicol 60: 312–314

    PubMed  CAS  Google Scholar 

  • Burchell B, Coughtrie MWH (1992) UDP-glucuronosyltransferases. In: Kalow W (ed) Pharmacogenetics of drug metabolism. Pergamon, New York, pp 95–165

    Google Scholar 

  • Chen ZR, Somogyi AA, Bochner F (1988) Polymorphic O-demethylation of codeine. Lancet 2: 914–915

    PubMed  CAS  Google Scholar 

  • Clark DWJ, Morgan AKW, Waal-Manning H (1984) Adverse effects from metoprolol are not generally associated with oxidation status. Br J Clin Pharmacol 18: 965–966

    PubMed  CAS  Google Scholar 

  • Cooper RG, Evans DAP, Whibley EJ (1984) Polymorphic hydroxylation of perhexiline maleate in man. J Med Genet 21: 27–33

    PubMed  CAS  Google Scholar 

  • Dahl-Puustinen ML, Liden A, Aim C, Nordin C, Bertilsson L (1989) Disposition of perphenazine is related to the polymorphic debrisoquine hydroxylation in human beings. Clin Pharmacol Ther 46: 78–81

    PubMed  CAS  Google Scholar 

  • Dayer P, Leemann T, Kiipfer A, Kronbach T, Meyer UA (1986) Stereo- and regioselectivity of hepatic oxidation in man—effect of the debrisoquine/sparteine phenotype on bufuralol hydroxylation. Eur J Clin Pharmacol 31: 313–318

    PubMed  CAS  Google Scholar 

  • 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 (cytochrome P-450 dbl/bufl). Biochem Biophys Res Commun 152: 4161–4165

    Google Scholar 

  • Deguchi T, Mashimo M, Suzuki T (1990) Correlation between acetylator phenotype and genotypes of polymorphic arylamine N-acetyltransferase in human liver. J Biol Chem 265: 12757–12760

    PubMed  CAS  Google Scholar 

  • Drayer DE, Reidenberg DM (1977) Clinical consequences of polymorphic acetylation of basic drugs. Clin Pharmacol Ther 22: 251–258

    PubMed  CAS  Google Scholar 

  • Ebner T, Eichelbaum M (1993) The metabolism of aprindine in relation to the sparteine/debrisoquine polymorphism. Br J Clin Pharmacol 35: 426–430

    PubMed  CAS  Google Scholar 

  • Eichelbaum M (1975) Ein neuentdeckter Defekt im Arzneimittelstoffwechsel des Menschen: Die fehlende N-Oxidation des Spartein. Habilitationsschrift, Friedrich-Wilhelms-University, Bonn

    Google Scholar 

  • Eichelbaum M, Gross AS (1992) The genetic polymorphism of debrisoquine sparteine metabolism—clinical aspects. In: Kalow W (ed) Pharmacogenetics of drug metabolism. Pergamon, New York, pp 625–643

    Google Scholar 

  • Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ (1979) Defective Noxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 16: 183–187

    PubMed  CAS  Google Scholar 

  • Eichelbaum M, Baur MP, Dengler HJ, Osikowska-Evers BO, Tieves G, Zekorn C, Rittner C (1987) Chromosomal assignment of human cytochrome P450 (debrisoquine/sparteine type) to chromosome 22. Br J Clin Pharmacol 23: 455–458

    PubMed  CAS  Google Scholar 

  • Evans DAP (1992) N-acetyltransferase. In: Kalow W (ed) Pharmacogenetics of drug metabolism. Pergamon, New York, pp 95–165

    Google Scholar 

  • Evans DAP, Manley KA, McKusick VA (1960) Genetic control of isoniazid metabolism in man. Br Med J 2: 485–461

    PubMed  CAS  Google Scholar 

  • Evans DAP, Mahgoub A, Sloan TP, Idle JR, Smith RL (1980) A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet 17: 102–105

    PubMed  CAS  Google Scholar 

  • Evans DAP, Eze LZ, Whibley EJ (1983) The association of the slow acetylator phenotype with bladder cancer. J Med Genet 20: 321–329

    PubMed  CAS  Google Scholar 

  • Feher MD, Lucas RA, Farid NA, Idle JR, Bergstrom RF, Lemberger L, Sever PS (1988) Single dose pharmacokinetics of tomoxetine in poor and extensive metabolisers of debrisoquine. Br J Clin Pharmacol 26: 231 P

    Google Scholar 

  • Fischer V (1992) Polymorphic drug metabolism and its consequences for drug development (Abstr). 13th European Workshop on Drug Metabolism, Bergamo

    Google Scholar 

  • Fischer V, Vogels B, Maurer G, Tynes RE (1992) The antipsychotic clozapine is metabolized by the polymorphic human microsomal and recombinant cytochrome P450 2D6. J Pharmacol Exp Ther 260: 1355–1360

    PubMed  CAS  Google Scholar 

  • Funck-Brentano C, Turgeon J, Woosley RL, Roden DM (1989) Effects of low dose quinidine on encainide pharmacokinetics and pharmacodynamics. Influence of genetic polymorphism. J Pharmacol Ther 249: 134–142

    CAS  Google Scholar 

  • Gaedigk A, Blum M, Gaedigk R, Eichelbaum M, Meyer UA (1991) 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: 943–950

    PubMed  CAS  Google Scholar 

  • Garrod AE (1902) The incidence of alcaptonuria: a study in chemical individuality. Lancet 2: 1616–1620

    CAS  Google Scholar 

  • Garrod AE (1931) The inborn factors of disease. Oxford University Press, London

    Google Scholar 

  • Ged C, Umbenhauer DR, Bellew TM, Bork RW, Srivastava PK, Shinriki N, Lloyd RS, Guengerich FP (1988) Characterization of cDNAs, mRNAs and proteins related to human liver microsomal cytochrome P450 S-mephenytoin 4-hydroxylase. Biochemistry 27: 6929–6940

    PubMed  CAS  Google Scholar 

  • Gleiter CH, Aichele G, Nilsson E, Hengen N, Antonin KH, Bieck PR (1985) Discovery of altered pharmacokinetics of CGP 15210G in poor hydroxylators of debrisoquine during early drug development. Br J Clin Pharmacol 20: 81–84

    PubMed  CAS  Google Scholar 

  • Goedde HW, Agarwal DP (1992) Pharmacogenetics of aldehyde dehydrogenase. In: Kalow W (ed) Pharmacogenetics of drug metabolism. Pergamon, New York, pp 281–314

    Google Scholar 

  • Gonzalez FJ (1992) Pharmacogenetics redefined. Trends Pharmacol Sci 13: 348

    Google Scholar 

  • Gonzalez FJ, Skoda RC, 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: 442–446

    PubMed  CAS  Google Scholar 

  • Gram LF (1975) Effects of perphenazine on imipramine metabolism in man. Psychopharmacol Commun 1: 165–175

    PubMed  CAS  Google Scholar 

  • Gram LF, Overo KF (1972) Drug interaction: inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants in man. Br Med J 163: 463 - 465

    Google Scholar 

  • 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: 272–275

    PubMed  CAS  Google Scholar 

  • Grant DM, Blum M, Demierre A, Meyer UA (1989) Nucleotide sequence for an intronless gene for a human arylamine Af-acetyltransferase related to polymorphic drug acetylation. Nucleic Acids Res 17: 3978

    PubMed  CAS  Google Scholar 

  • Grant DM, Mörike K, Eichelbaum M, Meyer UA (1990) Acetylation pharmacogenetics. The slow acetylator phenotype is caused by decreased or absent arylamine N-acetyltransferase in human liver. J Clin Invest 85: 968–972

    PubMed  CAS  Google Scholar 

  • Grant DM, Tang BK, Kalow W (1984) Polymorphic N-acetylation of a caffeine metabolite. Clin Pharmacol Ther 33: 355–359

    Google Scholar 

  • Guengerich FP, Distlerath LM, Reilly PEB, Wolff T, Shimada T, Umbenhauer DR, Martin MV (1986) Human-liver cytochromes P-450 involved in polymorphisms of drug oxidation. Xenobiotica 16: 367–378

    PubMed  CAS  Google Scholar 

  • Hall SD, Guengerich FP, Branch RA, Wilkinson GR (1987) Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes. J Pharmacol Exp Ther 240: 216–222

    PubMed  CAS  Google Scholar 

  • Heim M, Meyer UA (1990) Genotyping of poor metabolizers of debrisoquine by allele specific PCR-amplification. Lancet 336: 529–532

    PubMed  CAS  Google Scholar 

  • Heim M, Meyer UA (1992) Evolution of a highly polymorphic human cytochrome P450 gene cluster: CYP2D6. Genomics 14: 49–58

    PubMed  CAS  Google Scholar 

  • Hickman D, Risch A, Camilleri JP, Sim E (1992) Genotyping human arylamine N-acetyltransferase: identification of new allotypic variants. Pharmacogenetics 2: 217–226

    PubMed  CAS  Google Scholar 

  • Horai Y, Fujita K, Ishizaki T (1989) Genetically determined N-acetylation and oxidation capacities in Japanese patients with non occupational urinary bladder cancer. Eur J Clin Pharmacol 37: 581–587

    PubMed  CAS  Google Scholar 

  • Hori R, Okumura K, Inui KI, Yasuhara M, Yamada K, Sakurai T, Kawai C (1984) Quinidine-induced rise in ajmaline plasma concentration. J Pharm Pharmacol 36: 202–204

    PubMed  CAS  Google Scholar 

  • Hughes HB, Schmidt LH, Biehl JP (1955) The metabolism of isoniazide, its implications in therapeutic use. 14th Conference on Chemotherapy in Tuberculosis, Washington DC, US Veterans Adm Army Navy, pp 217–222

    Google Scholar 

  • Inaba T, Jurima M, Kalow W (1986) Family studies of mephenytoin hydroxylation deficiency. Am J Hum Genet 38: 768–772

    PubMed  CAS  Google Scholar 

  • Iselius L, Evans DAP (1983) Formal genetics of isoniazid metabolism in man. Clin Pharmacol Ther Clin Pharmacokinet 8: 541–544

    CAS  Google Scholar 

  • Islam SA, Wolf CR, Lennard MS, Sternberg MJE (1991) A three-dimensional molecular template for substrates of human cytochrome P450 involved in debrisoquine 4-hydroxylation. Carcinogenesis 12: 2211–2219

    PubMed  CAS  Google Scholar 

  • Jacqz E, Hall SD, Branch RA, Wilkinson GR (1986) Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a coregulated substrate, mephobarbital. Clin Pharmacol Ther 39: 646–653

    PubMed  CAS  Google Scholar 

  • Jenne JW (1965) Partial purification and properties of the isoniazide transacetylase in human liver: its relationship to the acetylation of para-amino salicylic acid. J Clin Invest 44: 1992–2002

    CAS  Google Scholar 

  • Jurima M, Inaba T, Kalow W (1985) Mephenytoin metabolism in vitro by human liver. Drug Metab Dispos 13: 151–155

    PubMed  CAS  Google Scholar 

  • Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA (1990) Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. J Biol Chem 265: 17209–17214

    PubMed  CAS  Google Scholar 

  • Kalow W (1956) Familial incidence of low pseudocholinesterase level. Lancet 2: 576–577

    Google Scholar 

  • Kalow W, Genest K (1957) A method for the detection of atypical forms of the human serum cholinesterase. Determination of dibucaine numbers. Can J Biochem Physiol 35: 339–346

    PubMed  CAS  Google Scholar 

  • Kalow W, Staron N (1957) On distribution and inheritance of atypical forms of human serum cholinesterase as indicated by dibucaine numbers. Can J Biochem Physiol 35: 1305–1320

    PubMed  CAS  Google Scholar 

  • Kitchen I, Tremblay J, Andre J, Dring LG, Idle JR, Smith RL, Williams RT (1979) Inter-individual and inter-species variation in the metabolism of the hallucinogen 4-methoxyamphetamine. Xenobiotica 9: 397–404

    PubMed  CAS  Google Scholar 

  • Knodell RG, Dubey RK, Wilkinson GR, Guengerich FP (1988) Oxidative metabolism of hexobarbital in human liver: relationship to polymorphic S-mephenytoin 4-hydroxylation. J Pharmacol Exp Ther 245: 845–849

    PubMed  CAS  Google Scholar 

  • 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: 28–33

    PubMed  CAS  Google Scholar 

  • Küpfer A, Branch RA (1985) Stereoselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation. Clin Pharmacol Ther 38: 414–418

    PubMed  Google Scholar 

  • Küpfer A, Preisig R (1984) Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 26: 753–759

    PubMed  Google Scholar 

  • Küpfer A, Schmid B, Preisig R, Pfaff G (1984) Dextromethorphan as a safe probe for debrisoquine hydroxylation polymorphism. Lancet 1: 517–518

    Google Scholar 

  • Lee JT, Kroemer HK, Silberstein DJ, Funck-Brentano C, Lineberry MD, Wood AJJ, Roden DM, Woosley RL (1990) The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone. N Engl J Med 322: 1764–1768

    PubMed  CAS  Google Scholar 

  • Leemann T, Dayer P, Meyer UA (1986) Single-dose quinidine treatment inhibits metoprolol oxidation in extensive metabolizers. Eur J Clin Pharmacol 29: 739–741

    PubMed  CAS  Google Scholar 

  • Lennard MS (1992) The polymorphic oxidation of β-adrenoceptor antagonists. In: Kalow W (ed) Pharmacogenetics of drug metabolism. Pergamon, New York, pp 701–720

    Google Scholar 

  • 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: 329–333

    PubMed  CAS  Google Scholar 

  • Llerena A, Dahl MJ, Ekqvist B, Bertilsson L (1992) Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype: increased plasma levels of the reduced metabolite in poor metabolizers. Ther Drug Monit 14: 261–264

    PubMed  CAS  Google Scholar 

  • Lockridge O (1992) Genetic variants of human serum butyrylcholinesterase influence the metabolism of the muscle relaxant succinylcholine. In: Kalow W (ed) Pharmacogenetics of drug metabolism. Pergamon, New York, pp 15–50

    Google Scholar 

  • Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet 2: 584–586

    PubMed  CAS  Google Scholar 

  • McGourty JC, Silas JH, Fleming JJ, McBurney A, Ward JW (1985) Pharmacokinetics and beta-blocking effects of timolol in poor and extensive metabolisers of debrisoquin. Clin Pharmacol Ther 38: 409–413

    PubMed  CAS  Google Scholar 

  • McGuire MC, Nogueira CP, Bartels CF, Lightstone H, Hajra A, van der Spek AFL, Lockridge O, La Du BN (1989) Identification of the structural mutation responsible for the dibucaine resistant (atypical) variant form of human serum cholinesterase. Proc Natl Acad Sci USA 86: 953–957

    PubMed  CAS  Google Scholar 

  • Meier UT, Meyer UA (1987) Genetic polymorphism of cytochrome P450 (5)-mephenytoin 4-hydroxylase. Studies with human autoantibodies suggest a functionally altered P450 enzyme as cause of genetic deficiency. Biochemistry 26: 8466–8474

    PubMed  CAS  Google Scholar 

  • Meier UT, Dayer P, Male PJ, Kronbach T, Meyer UA (1985) Mephenytoin hydroxylation polymorphism: characterization of the enzymatic deficiency in liver microsomes of poor metabolizers phenotyped in vivo. Clin Pharmacol Ther 38: 488–494

    PubMed  CAS  Google Scholar 

  • Mellström B, Bertilsson L, Lou Y-C, Sawe J, Sjoqvist F (1983) Amitryptiline metabolism: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 34: 516–520

    PubMed  Google Scholar 

  • Meyer UA, Gut J, Kronbach T, Skoda C, Meier UT, Catin T, Dayer P (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: 449–464

    PubMed  CAS  Google Scholar 

  • Meyer UA, Skoda RC, Zanger UM, Heim M, Broly F (1992) The genetic polymorphism of debrisoquine/sparteine polymorphism - molecular mechanisms. In: Kalow W (ed) Pharmacogenetics of drug metabolism. Pergamon, New York, pp 609–624

    Google Scholar 

  • Mitchell RS, Bell JC (1957) Clinical implications of isoniazide, PAS and streptomycin blood levels in pulmonary tuberculosis. Trans Am Clin Chem Assoc 69: 98–105

    Google Scholar 

  • Mörike K, Hardtmann E, Heimburg P (1990) Interindividual variation of N-propylajmaline dose requirement in patients with ventricular arrhythmia in relation to metabolic capacity of sparteine ( Abstr ). Naunyn Schmiedebergs Arch Pharmacol 341: 110

    Google Scholar 

  • Mortimer Ö, Lindstrom B, Laurell H, Bergman U, Rane A (1989) Dextromethorphan: polymorphic serum pattern of the O-demethylated and didemethylated metabolites in man. Br J Clin Pharmacol 27: 223–227

    PubMed  CAS  Google Scholar 

  • Motulsky AG (1957) Drug reactions, enzymes and biochemical genetics. JAMA 165: 835–837

    CAS  Google Scholar 

  • Nebert DW, Nelson DR, Feyereisen R, Fuji-Kuriyama Y, Coon MJ, Estabrook RW, Gonzolez FJ, Guengerich FP, Gunsalus IC, Johnson EF, Loper JC, Sato R, Waterman MR, Waxman DJ (1991) The P450 superfamily: update on new sequences, gene mapping and recommended nomenclature. DNA Cell Biol 10: 1–14

    PubMed  CAS  Google Scholar 

  • Nelson JC, Jatlow PI (1980) Neuroleptic effect on desipramine steady-state plasma concentrations. Am J Psychiatry 137: 1232–1234

    PubMed  CAS  Google Scholar 

  • Newton BW, Benson RC, McCarriston CC (1966) Sparteine sulphate: a potent capricious oxytocic. Am J Obstet Cynecol 94: 234–241

    CAS  Google Scholar 

  • Nordin C, Siwers B, Benitez J, Bertilsson L (1985) Plasma concentrations of nortriptyline and its 10-hydroxy metabolite in depressed patients—relationship to the debrisoquine hydroxylation ratio. Br J Clin Pharmacol 19: 832–835

    PubMed  CAS  Google Scholar 

  • Oates NS, Shah RR, Idle JR, Smith RL (1982) Genetic polymorphism of phenformin 4-hydroxylation. Clin Pharmacol Ther 32: 81–89

    PubMed  CAS  Google Scholar 

  • Okino ST, Quattrochi LC, Pendurthi UR, McBride OW, Tukey RH (1987) Characterization of multiple human cytochrome P4501 cDNAs: the chromosomal localization of the gene and evidence for alternate RNA splicing. J Biol Chem 262: 16072–16079

    PubMed  CAS  Google Scholar 

  • 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: 59–65

    PubMed  CAS  Google Scholar 

  • Raghuram TC, Koshakji RP, Wilkinson GR, Wood AJJ (1984) Polymorphic ability to metabolize propranolol alters 4-hydroxypropranolol levels but not beta blockade. Clin Pharmacol Ther 36: 51–56

    PubMed  CAS  Google Scholar 

  • Rane A, Modiri AR, Gerdin E (1992) Ethylmorphine O-deethylation cosegregates with the debrisoquin genetic metabolic polymorphism. Clin Pharmacol Ther 52: 257–264

    PubMed  CAS  Google Scholar 

  • Rao KVN, Mitchison DA, Nair NGK, Prema K, Tripathy SP (1970) Sulfadimidine acetylation test for classification of patients as slow or rapid inactivators of isoniazide. Br Med J 3: 495–497

    PubMed  CAS  Google Scholar 

  • Regardh CG, Johnson G (1984) Interindividual variations in metoprolol metabolism—some clinical and other observations. Br J Clin Pharmacol 17: 495–496

    PubMed  CAS  Google Scholar 

  • Robitzek EH, Selikoff IJ, Ornstein GG (1952) Chemotherapy of human tuberculosis with hydrazine derivatives of isonicotinic acid. Q Bull Sea View Hosp NY 13: 27–51

    CAS  Google Scholar 

  • Rost KL, Brosicke H, Brockmoller J, Scheffler M, Helge H, Roots I (1992) Increase of cytochrome P4501A2 activity by omeprazole: evidence by the 13C-[Af-3-methyl]-caffeine breath test in poor and extensive metabolizers of 5-mephenytoin. Clin Pharmacol Ther 52: 170–180

    PubMed  CAS  Google Scholar 

  • Roy SS, Hawes EM, McKay G, Korchinski ED, Midha KK (1985) Metabolism of methoxyphenamine in extensive and poor metabolisers of debrisoquin. Clin Pharmacol Ther 38: 128–133

    PubMed  CAS  Google Scholar 

  • Schmid B, Bircher J, Preisig R, Kiipfer A (1985) Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther 38: 618–624

    PubMed  CAS  Google Scholar 

  • Shah RR, Oates NS, Idle JR, Smith RL, Lockhart JDF (1982) Impaired oxidation of debrisoquine in patients with perhexiline neuropathy. Br Med J 284: 295–299

    CAS  Google Scholar 

  • Shah RR, Oates NS, Idle JR, Smith RL, Lockhart DF (1983) Prediction of subclinical perhexiline neuropathy in a patient with inborn error of debrisoquine hydroxylation. Am Heart J 105: 159–161

    PubMed  CAS  Google Scholar 

  • Shimada T, Misono KS, Guengerich FP (1986) Human liver microsomal cytochrome P450 mephenytoin hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism: purification and characterization of two similar forms involved in the reaction. J Biol Chem 261: 909–921

    PubMed  CAS  Google Scholar 

  • Siddoway LA, Thompson KA, McAllister B, Wang T, Wilkinson GR, Roden DM, Woosley RL (1987) Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 75: 785–791

    PubMed  CAS  Google Scholar 

  • Sindrup SH, Brosen K, Bjerring P, Arendt-Nielsen L, Larsen U, Angelo HR, Gram LF (1990) Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not in poor metabolizers of sparteine. Clin Pharmacol Ther 48: 686–693

    PubMed  CAS  Google Scholar 

  • Skjelbo E, Brosen K, Hallas J, Gram LF (1991) The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 49: 18–23

    PubMed  CAS  Google Scholar 

  • Skoda R, Gonzalez FJ, Demierre A, Meyer UA (1988) Two mutant alleles of the human cytochrome P450 dbl gene (P450 IID1) associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci USA 85: 5240–5243

    PubMed  CAS  Google Scholar 

  • Sloan TP, Mahgoub A, Lancaster R, Idle JR, Smith RL (1978) Polymorphism of carbon oxidation of drugs and clinical implications. Br Med J 2: 655–657

    PubMed  CAS  Google Scholar 

  • Srivastava PK, Yun CH, Beaune P, Ged C, Guengerich FP (1991) Separation of human liver microsomal tolbutamide hydroxylase and S-mephenytoin 4′-hydroxylase cytochrome P450 enzymes. Mol Pharmacol 40: 69–79

    PubMed  CAS  Google Scholar 

  • Vatsis KP, Martell KJ, Weber WW (1991) Diverse point mutations in the human gene for polymorphic N-acetyltransferase. Proc Natl Acad Sci USA 88: 6333–6337

    PubMed  CAS  Google Scholar 

  • Vogel F (1959) Moderne Probleme der Humangenetik. Ergeb Inn Med Kinderheilkol 12: 52–125

    Google Scholar 

  • Vogel F, Motulsky AG (1979) Human genetics. Springer, Berlin Heidelberg New York

    Google Scholar 

  • Von Bahr C, Movin G, Nordin C, Liden A, Hammarlund-Udenaes M, Hedberg A, Ring H, Sjoqvist F (1991) Plasma levels of thioridazine and metabolites are influenced by the debrisoquine hydroxylation phenotype. Clin Pharmacol Ther 49: 234–240

    Google Scholar 

  • Wagner F, Kalusche D, Trenk D, Jahnchen E, Roskamm H (1987) Drug interaction between propafenone and metoprolol. Br J Clin Pharmacol 24: 213–220

    PubMed  CAS  Google Scholar 

  • 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: 605–611

    PubMed  CAS  Google Scholar 

  • Ward SA, Walle T, Walle K, Wilkinson GR, Branch RA (1989) Propranolol’s metabolism is determined by both mephenytoin and debrisoquine hydroxylase activities. Clin Pharmacol Ther 45: 72–79

    PubMed  CAS  Google Scholar 

  • Ward SA, Helsby NA, Skjelbo E, Brosen K, Gram LF, Breckenridge AM (1991) The activation of the biguanide antimalarial proguanil cosegregates with the mephenytoin oxidation polymorphism—a panel study. Br J Clin Pharmacol 31: 689–692

    PubMed  CAS  Google Scholar 

  • Wedlund PJ, Aslani WS, McAllister CB, Wilkinson GR, Branch RA (1984) Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 36: 773–780

    PubMed  CAS  Google Scholar 

  • Weinshilbaum R (1992) Methyltransferase pharmacogenetics. In: Kalow W (ed) Pharmacogenetics of drug metabolism. Pergamon, New York, pp 179–194

    Google Scholar 

  • Wilkinson GR, Guengerich FP, Branch RA (1992) Genetic polymorphism of S-mephenytoin hydroxylation. In: Kalow W (ed) Pharmacogenetics of drug metabolism. Pergamon, New York, pp 657–680

    Google Scholar 

  • Woosley RL, Drayer DE, Reidenberg MM, Nies AS, Carr K, Oates JA (1978) Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome. N Engl J Med 298: 1157–1159

    PubMed  CAS  Google Scholar 

  • Zekorn C, Achtert G, Hausleiter HJ, Moon CH, Eichelbaum M (1985) Pharmacokinetics of TV-propylajmaline in relation to polymorphic sparteine oxidation. Klin Wochenschr 63: 1180–1186

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. H. K. Kroemer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Mikus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Eichelbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Pharmacokinetics/Drug Metabolism Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, 2800 Plymouth Road, 48105-1047, Ann Arbor, MI, USA

    Peter G. Welling Ph.D., D.Sc. (Vice President) (Vice President)

  2. Clinical Research Unit, Department of Psychiatry, 47, Rue du XXXI Décembre, CH-1207, Geneva, Switzerland

    Luc P. Balant Ph.D. (Reader) (Reader)

Rights and permissions

Reprints and permissions

Copyright information

© 1994 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Kroemer, H.K., Mikus, G., Eichelbaum, M. (1994). Clinical Relevance of Pharmacogenetics. In: Welling, P.G., Balant, L.P. (eds) Pharmacokinetics of Drugs. Handbook of Experimental Pharmacology, vol 110. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-78680-8_9

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-78680-8_9

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-78682-2

  • Online ISBN: 978-3-642-78680-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation