Skip to main content
SpringerLink
Log in

Relationships Between Debrisoquine Hydroxylation and Propafenone Pharmacokinetics

  • Original Research Article
  • Published:
Drug Investigation Aims and scope Submit manuscript

Summary

The aims of this study were to evaluate the oxidising phenotype in a random sample of the Italian population and to study the relationships between the phenotype and the pharmacokinetics of propafenone, which is oxidised to 5-hydroxypropafenone.

The urinary debrisoquine: 4-hydroxydebrisoquine ratio was used to characterise the oxidative phenotype in 90 subjects (42 patients with ventricular arrhythmias and 48 healthy volunteers); subjects with ratios higher than 12.6 were defined ‘poor metabolisers’. The pharmacokinetics of propafenone were studied in 10 ‘extensive metabolisers’ of debrisoquine, both after acute and maintenance administration.

The incidence of ‘poor metabolisers’ was 6.6%, similar to that of other studies in Caucasians. Propafenone exibited nonlinear kinetics; the propafenone: 5-hydroxypropafenone ratio and the propafenone half-life were significantly related to the debrisoquine: 4-hydroxydebrisoquine ratio, both after single dose (r = 0.97; r = 0.96, respectively) and maintenance administration (r = 0.99; r = 0.95).

In conclusion, the differences in oxidising capacity observed among ‘extensive me-tabolisers’ markedly influence the kinetics of propafenone with relevant clinical implications.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Boobis AR, Murray S, Kahn C, Robertz GM, Davies DS. Substrate specificity of the form of cytochrome P-450 catalyzing the 4-hydroxylation of debrisoquine in man. Molecular Pharmacology 23: 474–481, 1983

    PubMed  CAS  Google Scholar 

  • Brode E, Sachse R, Hoffmann HD. Untersuchungen zur Analytik von Propafenon mittels interner Analogstandardsierung. Arzneimittel Forschung 32: 1–6, 1982

    PubMed  CAS  Google Scholar 

  • Capucci A, Gubelli S, Carini G, Frabetti L, Magnani B. Cardioversione farmacologica con propafenone di fibrillazione atriale stabile di recente insorgenza. Giornale Italiano di Cardiologia 17: 975–982, 1987

    PubMed  CAS  Google Scholar 

  • Connolly SJ, Kates RE, Lebsack CS, Harrison DC, Winkle RA. Clinical pharmacology of propafenone. Circulation 68: 589–596, 1983

    Article  PubMed  CAS  Google Scholar 

  • Connolly S, Lebsack C, Winkle RA, Harrison DC, Kates RE. Propafenone disposition kinetics in cardiac arrhythmia. Clinical Pharmacology and Therapeutics 36: 163–168, 1984

    Article  PubMed  CAS  Google Scholar 

  • Clark DWJ. Genetically determined variability in acetylation and oxidation: therapeutic implications. Drugs 29: 342–375, 1985

    Article  PubMed  CAS  Google Scholar 

  • Frabetti L, Marchesini B, Capucci A, Cavallini C, Gubelli S, et al. Antiarrhythmic efficacy of propafenone: evaluation of effective plasma levels following single and multiple doses. European Journal of Clinical Pharmacology 30: 665–671, 1986

    Article  PubMed  CAS  Google Scholar 

  • Hammill SC, McLaran CJ, Wood DL, Osborn MJ, Gersh BJ, et al. Double blind study of intravenous propafenone for paroxysmal supra ventricular reentrant tachycardia. Journal of the American College of Cardiology 9: 1364–1368, 1987

    Article  PubMed  CAS  Google Scholar 

  • Hammill SC, Sorenson PB, Wood DL, Sugrue DD, Osborn MJ, et al. Propafenone for the treatment of refractory complex ventricular ectopic activity. Mayo Clinic Proceedings 61: 98–103, 1986

    PubMed  CAS  Google Scholar 

  • Harrison PM, Tonkin AM, Dixon ST, McLean AJ. Determination of debrisoquine and its 4-hydroxy metabolite in urine by high-performance liquid chromatography. Journal of Chromatography 374: 204–208, 1986

    Article  PubMed  CAS  Google Scholar 

  • Harron DWG, Brogden RN. Propafenone: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in the treatment of arrhythmias. Drugs 34: 617–647, 1987

    Article  PubMed  CAS  Google Scholar 

  • Hege HG, Hollman M, Kaumeier S, Lietz H. The metabolic fate of 3H-labelled propafenone in man. European Journal of Drug Metabolism and Pharmacokinetics 9: 41–55, 1984

    Article  PubMed  CAS  Google Scholar 

  • Horai Y, Ishizaki T. Pharmacogenetics and its clinical implications, part II: oxidation polymorphisms. Rational Drug Therapy 22: 1–8, 1988

    PubMed  CAS  Google Scholar 

  • Islam SI, Idle JR, Smith RL. The polymorphic 4-hydroxylation of debrisoquine in a Saudi Arabian population. Xenobiotica 10: 819–825, 1980

    Article  PubMed  CAS  Google Scholar 

  • Kalow W. Ethnic differences in drug metabolism. Clinical Pharmacokinetics 7: 373–400, 1982

    Article  PubMed  CAS  Google Scholar 

  • Kates RE, Yee YG, Winkle RA. Metabolite cumulation during chronic propafenone dosing in arrhythmias. Clinical Pharmacology and Therapeutics 37: 610–614, 1985

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Mahgoub A, Idle JR, Smith RL. A population and familial study of the defective alicyclic hydroxylation of debrisoquine among Egyptians. Xenobiotica 9: 51–56, 1979

    Article  PubMed  CAS  Google Scholar 

  • Marchesini B, Tornasi L. Effects of modifiers on the Chromatographic behaviour of propafenone and its major metabolite. Chromatographia 34: 753–758, 1987

    Article  Google Scholar 

  • Mbanefo C, Bababunmi EA, Mahgoub A, Sloan TP, Idle JR, et al. A study of the debrisoquine hydroxylation polymorphism in a Nigerian population. Xenobiotica 10: 811–818, 1980

    Article  PubMed  CAS  Google Scholar 

  • Nakamura K, Goto F, Ray WA, McAllister CB, Jacqz E, et al. Interethnic differences in genetic polymorphism of debrisoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Clinical Pharmacology and Therapeutics 38: 402–408, 1985

    Article  PubMed  CAS  Google Scholar 

  • Podrid PJ, Cytryn R, Lown B. Propafenone: noninvasive evaluation of efficacy. American Journal of Cardiology 54: 53D–59D, 1984

    Article  PubMed  CAS  Google Scholar 

  • Price Evans DA, Mahgoub A, Sloan TP, Idle JR, Smith RL. A family and population study on the genetic polymorphism of debrisoquine oxidation in a white British population. Journal of Medical Genetics 17: 102–105, 1980

    Article  Google Scholar 

  • Siddoway LA, Thompson KA, McAllister B, Wang T, Wilkinson GR, et al. Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 75: 785–791, 1987

    Article  PubMed  CAS  Google Scholar 

  • Sloan TP, Lancaster R, Shah RR, Idle JR, Smith RL. Genetically determined oxidation capacity and the disposition of debrisoquine. British Journal of Clinical Pharmacology 15: 443–450, 1983

    Article  PubMed  CAS  Google Scholar 

  • Steiner E, Iselius L, Alvan G, Lindsten J, Sjoqvist F. A family study of genetic and environmental factors determining polymorphic hydroxylation of debrisoquin. Clinical Pharmacology and Therapeutics 38: 394–401, 1985

    Article  PubMed  CAS  Google Scholar 

  • Steiner E, Bertilsson L, Sawe J, Bertling I, Sjoqvist F. Polymorphic debrisoquin hydroxylation in 757 Swedish subjects. Clinical Pharmacology and Therapeutics 44: 431–435, 1988

    Article  PubMed  CAS  Google Scholar 

  • Valenzuela C, Delgado C, Tamargo J. Electrophysiological effects of 5-hydroxypropafenone on guinea pig ventricular muscle fibers. Journal of Cardiovascular Pharmacology 10: 523–529, 1987

    Article  PubMed  CAS  Google Scholar 

  • Von Philisborn G, Gries J, Hofmann HP, Kreiskott R, Kretzchmar R, et al. Pharmacological studies on propafenone and its main metabolite 5- hydroxypropafenone. Arzneimittel Forschung 34: 1489–1497, 1984

    Google Scholar 

  • Woolhouse NM, Andoh B, Mahgoub A, Sloan TP, Idle JR, et al. Debrisoquine hydroxylation polymorphism among Ghananians and Caucasians. Clinical Pharmacology and Therapeutics 26: 584–591, 1979

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Istituto di Malattie dell’Apparato Cardiovascolare, Via Massarenti 9, 40138, Bologna, Italy

    G. Boriarti, A. Capucci & B. Magnani

  2. Cattedra di Terapia Medica Sistematica, Universita di Bologna, Bologna, Italy

    E. Strocchi, S. Boschi, B. Marchesini & E. Ambrosioni

Authors
  1. G. Boriarti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Strocchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Capucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Boschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B. Marchesini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Ambrosioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B. Magnani
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boriarti, G., Strocchi, E., Capucci, A. et al. Relationships Between Debrisoquine Hydroxylation and Propafenone Pharmacokinetics. Drug Invest 2, 114–119 (1990). https://doi.org/10.1007/BF03258249

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03258249

Keywords

Search

Navigation