Summary
The aim of the study was to validate a test based on analyses of urine to identify the propafenone metaboliser phenotype during routine chronic therapy. Twenty seven patients chronically treated with propafenone were studied. A debrisoquine test was performed in 10. Propafenone and its metabolites in plasma and urine were measured by HPLC. Propafenone, 5-hydroxypropafenone and N-depropylpropafenone concentrations in plasma were 1.09, 0.182 and 0.101 ng·ml−1, respectively. Total recovery of the administered dose in urine was 30.7%. Two patients were identified as PM, based on the result of the debrisoquine test (log D/4OHD of 1.26 and 1.36). This finding was confirmed by the propafenone metabolic ratio in urine, but the plasma data did not permit clearcut separation of the phenotypes. Propafenone/5-hydroxypropafenone in plasma was not a good predictor of metabolizer phenotype. Although the number of patients who completed all three tests was limited, it is concluded that analysis of propafenone/5-hydroxypropafenone in urine collected between two consecutive doses at steady-state is more practical than the debrisoquine test and more specific than determining the propafenone/5-hydroxypropafenone ratio in plasma, for identification of the propafenone metaboliser phenotypes.
This is a preview of subscription content, log in via an institution to check access.
References
Harron DWG, Brogden RN (1987) Propafenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias. Drugs 34: 617–647
Funck-Brentano C, Kroemer HK, Lee JT, Roden DM (1990) Propafenone. N Engl J Med 322: 518–525
Thompson KA, Iansmith DHS, Siddoway LA, Woosley RL, Roden DM (1988) Potent electrophysiologic effects of the major metabolites of propafenone in canine Purkinje fibers. J Pharmacol Exp Ther 244: 950–955
Malfatto G, Zaza A, Forster M, Sodowick B, Danilo P Jr, Rosen MR (1988) Electrophysiologic, inotropic and antiarrhythmic effects of propafenone, 5-hydroxypropafenone and N-depropylpropafenone. J Pharmacol Exp Ther 246: 419–426
Siddoway LA, Thompson KA, McAllister CB, Wang T, Wilkinson GR, Roden DM, Woosley RL (1987) Polimorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 75: 785–791
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
Boriani G, Strocchi E, Capucci A, Boschi S, Marchesini B, Ambrosioni E, Magnani B (1990) Relationships between debrisoquine hydroxylation and propafenone pharmacokinetics. Drug Invest 2: 114–119
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
Funck-Brentano C, Kroemer HK, Pavlou H, Woosley RL, Roden DM (1989) Genetically-determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect. Br J Clin Pharmacol 27: 435–444
Brosen K, Gram LF (1989) Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol 36: 537–547
Latini R, Sica A, Marchi S, Chen ZM, Gavinelli M, Benfenati E (1988) High-performance liquid chromatographic separation and mass spectrometric identification of propafenone, 5-hydroxypropafenone and N-depropylpropafenone. J Chromatogr 424: 211–214
Lennard MS, Silas JH, Smith AJ, Tucker GT (1977) Determination of debrisoquine and its 4-hydroxy metabolite in biological fluids by gas chromatography with flame-ionization and nitrogen-selective detection. J Chromatogr 133: 161–166
Wagner F, Jähnchen E, Trenk D, Eichelbaum M, Harnasch P, Hauf G, Roskamm H (1987) Severe complications of antianginal drug therapy in a patient identified as a poor metabolizer of metoprolol, propafenone, diltiazem, and sparteine. Klin Wochenschr 65: 1164–1168
Kates RE, Yee YG, Winkle RA (1985) Metabolite cumulation during chronic propafenone dosing in arrhythmia. Clin Pharmacol Ther 37: 610–614
Giani P, Landolina M, Giudici V, Bianchini C, Ferrario G, Marchi S, Riva E, Latini R (1988) Pharmacokinetics and pharmacodynamics of propafenone during acute and chronic administration. Eur J Clin Pharmacol 34: 187–194
Vozeh S, Haefeli W, Ha H-R, Vlcek J, Follath F (1990) Nonlinear kinetics of propafenone metabolites in healthy man. Eur J Clin Pharmacol 38: 509–513
Hege HG, Hollmann M, Kaumeier S, Lietz H (1984) The metabolic fate of 2H-labelled propafenone in man. Eur J Drug Metab Pharmacokinet 9: 41–55
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Latini, R., Belloni, M., Bernasconi, R. et al. Identification of propafenone metaboliser phenotype from plasma and urine excretion data. Eur J Clin Pharmacol 42, 111–114 (1992). https://doi.org/10.1007/BF00314930
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00314930