Inhibition of Desipramine 2-Hydroxylation by Quinidine and Quinine in Rapid and Slow Debrisoquine Hydroxylators

  • E. Spina
  • E. Steiner
  • E. Dumont
  • R. Dahlqvist
Conference paper
Part of the Psychopharmacology Series book series (PSYCHOPHARM, volume 7)

Abstract

Polymorphic oxidation has been described for debrisoquine (Mahgoub et al. 1977) and for sparteine (Eichelbaum et al. 1979). Reduced ability to oxidize these compounds is inherited as an autosomal recessive trait (Price-Evans et al. 1980), and the prevalence of the slow hydroxylator phenotype varies between 3% and 9%, depending on the country (Eichelbaum 1982). Biochemical studies indicate that this polymorphism is caused by an inherited absence or functional deficiency of a particular cytochrome P-450 isozyme, called debrisoquine hydroxylase (Boobies et al. 1983). The oxidative metabolism of several other drugs has been shown to cosegregate with the debrisoquine/sparteine oxidation polymorphism (Jacqz et al. 1986).

Keywords

HPLC Dine Cimetidine Tricyclic Metoprolol 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Boobis AR, Murray S, Kahn GC, Robertz GM, Davies DS (1983) Substrate specificity of the form of cytochrome P-450 catalyzing the 4-hydroxylation of debrisoquine in man. Mol Pharmacol 23: 474–481PubMedGoogle Scholar
  2. Brinn R, Brøsen K, Gram LF, Haghfelt T, Otton V (1986) Sparteine oxidation is practically abolished in quinidine-treated patients. Br J Clin Pharmacol 22: 194–197PubMedGoogle Scholar
  3. Brøsen K, Gram LF, Haghfelt T, Bertilsson L (1987) Extensive metabolizers of debrisoquine become poor metabolizers during quinidine treatment. Pharmacol Toxicol 60: 312–314PubMedCrossRefGoogle Scholar
  4. Eichelbaum M (1982) Defective oxidation of drugs: pharmacokinetic and therapeutic implications. Clin Pharmacokinet 7: 1–22PubMedCrossRefGoogle Scholar
  5. Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ (1979) Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 16: 183–187PubMedCrossRefGoogle Scholar
  6. Inaba T, Tyndale RE, Mahon WA (1986) Quinidine: potent inhibition of sparteine and debrisoquine oxidation in vivo. Br J Clin Pharmacol 22: 199–200PubMedGoogle Scholar
  7. Jacqz E, Hall SD, Branch RA (1986) Genetically determined polymorphisms in drug oxida¬tion. Hepatology 6: 1020–1032PubMedCrossRefGoogle Scholar
  8. Leemann T, Dayer P, Meyer UA (1986) Single-dose quinidine treatment inhibits metoprolol oxidation in extensive metabolizers. Eur J Clin Pharmacol 29: 739–741PubMedCrossRefGoogle Scholar
  9. Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet 2: 584–586PubMedCrossRefGoogle Scholar
  10. Mikus G, Ha HR, Vozeh S, Zekorn C, Follath F, Eichelbaum M (1986) Pharmacokinetics and metabolism of quinidine in extensive and poor metabolizers of sparteine. Eur J Clin Pharmacol 31: 69–72PubMedCrossRefGoogle Scholar
  11. Otton SV, Inaba T, Kalow W (1984) Competitive inhibition of sparteine oxidation in human liver by β-adrenoceptor antagonists and other cardiovascular drugs. Life Sci 34: 73–80PubMedCrossRefGoogle Scholar
  12. Otton SV, Brinn RU, Gram LF (1986) Quinidine 3-hydroxylase activity in human liver microsomes: effect of added debrisoquine, sparteine and desipramine (Abstr no 318). Acta Pharmacol Toxicol (Copenh) [Suppl 5] 59: 113Google Scholar
  13. Price-Evans DA, 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: 102–105CrossRefGoogle Scholar
  14. Speirs CJ, Murray S, Boobis AR, Seddon CE, Davies DS (1986) Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine. Br J Clin Pharmacol 22: 739–743PubMedGoogle Scholar
  15. Spina E (1987) Hydroxylation of desmethylimipramine in man. Thesis, Karolinska Institute, StockholmGoogle Scholar
  16. Spina E, Birgersson C, von Bahr C, Ericsson O, Mellstrom B, Steiner E, Sjoqvist F (1984) Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes. Clin Pharmacol Ther 36: 677–682PubMedCrossRefGoogle Scholar
  17. Spina E, Steiner E, Ericsson O, Sjoqvist F (1987) Hydroxylation of desmethylimipramine: dependence on the debrisoquine hydroxylation phenotype. Clin Pharmacol Ther 41: 314–319PubMedCrossRefGoogle Scholar
  18. Steiner E, Spina E (1987) Differences in the inhibitory effect of Cimetidine on desipramine metabolism between rapid and slow debrisoquine hydroxylators. Clin Pharmacol Ther 42: 278–282PubMedCrossRefGoogle Scholar
  19. Steiner E, Dumont E, Spina E, Dahlqvist R (1988) Inhibition of desipramine 2-hydroxylation by quinidine and quinine. Clin Pharmacol Ther 43: 577–581PubMedCrossRefGoogle Scholar
  20. Sutfin TA, Jusko WJ (1979) High-performance liquid chromatographic assay for Imipramine, desipramine and their 2-hydroxylated metabolites. J Pharm Sci 68: 703–705PubMedCrossRefGoogle Scholar
  21. Von Bahr C, Spina E, Birgersson C, Ericsson O, Goransson M, Henthorn T, Sjöqvist F (1985) Inhibition of desmethylimipramine 2-hydroxylation by drugs in human liver microsomes. Biochem Pharmacol 34: 2501–2505CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1989

Authors and Affiliations

  • E. Spina
    • 1
  • E. Steiner
    • 2
  • E. Dumont
    • 2
  • R. Dahlqvist
    • 2
  1. 1.Institute of PharmacologyUniversity of MessinaMessinaItaly
  2. 2.Department of Clinical Pharmacology, Karolinska InstituteHuddinge University HospitalHuddingeSweden

Personalised recommendations