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Influence of debrisoquine hydroxylation phenotype on the pharmacokinetics of mexiletine

European Journal of Clinical Pharmacology volume 44, pages 63–67 (1993)Cite this article

Summary

Marked interindividual variation has been observed in the pharmacokinetics of the antiarrhythmic agent mexiletine. The fact that its urinary excretion is dependent on urinary pH may account, in part, for such variation. The influence that genetic differences in hepatic metabolism of the debrisoquine-type may have on mexiletine pharmacokinetics was considered in this study. The pharmacokinetics and urinary excretion of mexiletine (250 mg administered intravenously) were investigated in 5 rapid extensive metabolisers (EM), 5 slow EM and 5 poor metabolisers (PM) of debrisoquine, under conditions of controlled urinary pH.

Mexiletine disposition kinetics was found to be altered in PM individuals. These subjects showed higher total area under the curve (AUC), (15.7 versus 8.16 μg · h · ml−1) prolonged elimination half-lives (in serum and urine) (serum: 18.5 versus 11.6 h, urine: 19.2 versus 11.7 h) and lower total clearance values compared with EM (216 versus 450 ml · min−1). In this respect, slow EM individuals generally presented intermediate values of those pharmacokinetic parameters. A higher incidence of adverse-effects was also observed among slow EM and PM subjects.

It is concluded that genetic differences in mexiletine oxidation of the debrisoquine-type have an influence on its observed pharmacokinetic variability. The clinical consequences are discussed.

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References

  1. Kiddie MA, Royds RB, Shaw TRD (1973) Preliminary studies on the pharmacology of an antidysrhythmic, kö1173, in man. Br J Clin Pharmacol 47: 674P

  2. Talbot RG, Clark RA, Nimmo J, Neilson JMM, Julian DG, Prescott LF (1973) Treatment of ventricular arrhythmias with mexiletine (kö1173). Lancet II: 399–404

    Google Scholar 

  3. Kaye CM, Kiddie MA, Turner P (1977) Variable pharmacokinetics of mexiletine. Postgrad Med J 53 [Suppl 1]: 56–58

    Google Scholar 

  4. Otton SV, Inaba T, Kalow W (1984) Competitive inhibition of sparteine oxidation in human liver by beta-adrenoceptor antagonists and other cardiovascular drugs. Life Sciences 34: 73–80

    Google Scholar 

  5. Brøsen K, Klysner R, Gram LF, Otton SV, Bech P, Bertilsson L (1986) Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism. Eur J Clin Pharmacol 30: 679–684

    Google Scholar 

  6. Lledó-Polo MP (1991) PhD Dissertation, University of London

  7. Barbeau A, Roy M, Paris S, Cloutier T, Plasse L, Poirier J (1985) Ecogenetics of Parkinson's disease: 4-hydroxylation of debrisoquine. Lancet: 1213–1215

  8. Kiddie MA, Kaye CM, Turner P, Shaw TRD (1974) The influence of urinary pH on the elimination of mexiletine. Br J Clin Pharmacol 1: 229–232

    Google Scholar 

  9. Johnston A, Burgess CD, Warrington SJ, Hamer NAJ (1979) The effect of spontaneous changes in urinary pH on mexiletine plasma concentrations and excretion during chronic administration to healthy volunteers. Br J Clin Pharmacol 8: 349–352

    Google Scholar 

  10. Johnston A, Woollard RC (1983) STRIPE: and interactive computer program for the analysis of drug pharmacokinetics. J Pharmacol Methods 9: 193

    Google Scholar 

  11. Podrid PJ (1986) New antiarrhythmic drugs: contrast and comparison. In: Baskf K, Corporation F (eds) The new pharmacotherapy of arrhythmia management: focus on propafenone (Monograph) pp 17–20

  12. Campbell NPS, Pantridge JF, Adgey AAJ (1978) Long term oral antiarrhythmic therapy with mexiletine. Br Heart J 40: 796–801

    Google Scholar 

  13. Beckett AH, Chidomere EC (1977) The distribution, metabolism and excretion of mexiletine in man. Postgrad Med J 53 [Suppl 1]: 60–66

    Google Scholar 

  14. Lledó P, Abrams SML, Johnston A, Pearson RM (1990) Mexiletine pharmacokinetics and debrisoquine hydroxylator status. Eur J Pharmacol 183: 2387

    Google Scholar 

  15. Lledó P, Abrams SML, Johnston A, Pearson RM (1991) Mexiletine elimination and debrisoquine hydroxylator status. Br J Clin Pharmacol 30: 598P

  16. Broly F, Vandamme N, Libersa C, Lhermitte M (1991) The metabolism of mexiletine in relation to the debrisoquine/sparteine-type polymorphism of drug oxidation. Br J Clin Pharmacol 32: 459–466

    Google Scholar 

  17. Lennard MS, Tucker GT, Silas JH, Freestone S, Ramsay LE, Woods HF (1983) Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquine metabolisers. Clin Pharmacol Ther 34: 732–737

    Google Scholar 

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

    Google Scholar 

  19. Meyer UA, Gut J, Kronbach T, Skoda C, Meier UT, Catin T (1986) The molecular mechanisms of two common polymorphisms of drug oxidation — evidence for functional changes in cytochrome P-450 isozymes catalysing bufuralol and mephenytoin oxidation. Xenobiotica 16: 449–464

    Google Scholar 

  20. Gould AC, Amoah AGB, Park DV (1986) Stereoselective pharmacokinetics of perhexiline. Xenobiotica 16: 491–502

    Google Scholar 

  21. Meese CO, Eichelbaum M (1988) Stereoselective drug metabolism and pharmacodynamic consequences. In: Kato R, Estabrook RW, Cayen MN (eds) Xenobiotic metabolism and disposition. Taylor & Francis, London, pp 179–184

    Google Scholar 

  22. Nitsch J, Steinbeck G, Luderitz B (1983) Increase of mexiletine plasma levels due to delayed hepatic metabolism in patients with chronic liver disease. Eur Heart J 4: 810–814

    Google Scholar 

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Affiliations

  1. Department of Clinical Pharmacology, St. Bartholomew's Hospital, London, UK

    P. Lledó, S. M. L. Abrams, A. Johnston, M. Patel, R. M. Pearson & P. Turner

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  1. P. Lledó
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  2. S. M. L. Abrams
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  3. A. Johnston
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  4. M. Patel
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  5. R. M. Pearson
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  6. P. Turner
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Lledó, P., Abrams, S.M.L., Johnston, A. et al. Influence of debrisoquine hydroxylation phenotype on the pharmacokinetics of mexiletine. Eur J Clin Pharmacol 44, 63–67 (1993). https://doi.org/10.1007/BF00315282

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  • DOI: https://doi.org/10.1007/BF00315282

Key words

  • Mexiletine
  • Debrisoquine hydroxylation phenotype
  • pharmacokinetic
  • variability