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. 1990 Mar;29(3):299–304. doi: 10.1111/j.1365-2125.1990.tb03639.x

A dose-effect study of the in vivo inhibitory effect of quinidine on sparteine oxidation in man.

M D Nielsen 1, K Brøsen 1, L F Gram 1
PMCID: PMC1380129  PMID: 2310654

Abstract

1. Twelve healthy extensive metabolisers of sparteine were sparteine tested daily for 6 days (19.00 h to 07.00 h). A small but statistically significant rise in sparteine metabolic ratio (MR) was observed. 2. Following 100 mg quinidine sulphate given to four of the subjects at 16.00 h, sparteine tests were carried out 19.00 h to 07.00 h on the same day and then daily for 6 days. Quinidine caused an immediate twenty-fold increase in sparteine-MR which then gradually returned to normal over the following 4-6 days. Quinidine concentrations in plasma were measurable only up to 20 h after the quinidine test dose. 3. At weekly intervals, all 12 subjects received single doses of quinidine sulphate of 5, 10, 20, 40 and 80 mg at 16.00 h, each time followed by a sparteine test 19.00 h to 07.00 h on the same day. A clear dose-effect relationship was found with a significant rise in the sparteine-MR even after 5 mg quinidine. After 80 mg quinidine, 8 of 12 subjects became phenotypically poor metabolisers (MR greater than 20).

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Brinn R., Brøsen K., Gram L. F., Haghfelt T., Otton S. V. Sparteine oxidation is practically abolished in quinidine-treated patients. Br J Clin Pharmacol. 1986 Aug;22(2):194–197. doi: 10.1111/j.1365-2125.1986.tb05250.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brøsen K., Davidsen F., Gram L. F. Quinidine kinetics after a single oral dose in relation to the sparteine oxidation polymorphism in man. Br J Clin Pharmacol. 1990 Feb;29(2):248–253. doi: 10.1111/j.1365-2125.1990.tb03628.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brøsen K., Gram L. F. Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol. 1989;36(6):537–547. doi: 10.1007/BF00637732. [DOI] [PubMed] [Google Scholar]
  4. Brøsen K., Gram L. F., Haghfelt T., Bertilsson L. Extensive metabolizers of debrisoquine become poor metabolizers during quinidine treatment. Pharmacol Toxicol. 1987 Apr;60(4):312–314. doi: 10.1111/j.1600-0773.1987.tb01758.x. [DOI] [PubMed] [Google Scholar]
  5. Brøsen K., Gram L. F. Quinidine inhibits the 2-hydroxylation of imipramine and desipramine but not the demethylation of imipramine. Eur J Clin Pharmacol. 1989;37(2):155–160. doi: 10.1007/BF00558224. [DOI] [PubMed] [Google Scholar]
  6. Brøsen K., Klysner R., Gram L. F., Otton S. V., Bech P., Bertilsson L. Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism. Eur J Clin Pharmacol. 1986;30(6):679–684. doi: 10.1007/BF00608215. [DOI] [PubMed] [Google Scholar]
  7. Brøsen K., Otton S. V., Gram L. F. Sparteine oxidation polymorphism in Denmark. Acta Pharmacol Toxicol (Copenh) 1985 Nov;57(5):357–360. doi: 10.1111/j.1600-0773.1985.tb00058.x. [DOI] [PubMed] [Google Scholar]
  8. Brøsen K., Otton S. V., Gram L. F. Sparteine oxidation polymorphism: a family study. Br J Clin Pharmacol. 1986 Jun;21(6):661–667. doi: 10.1111/j.1365-2125.1986.tb05231.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eichelbaum M., Spannbrucker N., Steincke B., Dengler H. J. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol. 1979 Sep;16(3):183–187. doi: 10.1007/BF00562059. [DOI] [PubMed] [Google Scholar]
  10. Evans D. A., Harmer D., Downham D. Y., Whibley E. J., Idle J. R., Ritchie J., Smith R. L. The genetic control of sparteine and debrisoquine metabolism in man with new methods of analysing bimodal distributions. J Med Genet. 1983 Oct;20(5):321–329. doi: 10.1136/jmg.20.5.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Evans D. A., Mahgoub A., Sloan T. P., Idle J. R., Smith R. L. A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet. 1980 Apr;17(2):102–105. doi: 10.1136/jmg.17.2.102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gonzalez F. J., Skoda R. C., Kimura S., Umeno M., Zanger U. M., Nebert D. W., Gelboin H. V., Hardwick J. P., Meyer U. A. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature. 1988 Feb 4;331(6155):442–446. doi: 10.1038/331442a0. [DOI] [PubMed] [Google Scholar]
  13. Gram L. F., Bjerre M., Kragh-Sørensen P., Kvinesdal B., Molin J., Pedersen O. L., Reisby N. Imipramine metabolites in blood of patients during therapy and after overdose. Clin Pharmacol Ther. 1983 Mar;33(3):335–342. doi: 10.1038/clpt.1983.42. [DOI] [PubMed] [Google Scholar]
  14. Guengerich F. P., Müller-Enoch D., Blair I. A. Oxidation of quinidine by human liver cytochrome P-450. Mol Pharmacol. 1986 Sep;30(3):287–295. [PubMed] [Google Scholar]
  15. Inaba T., Jurima M., Mahon W. A., Kalow W. In vitro inhibition studies of two isozymes of human liver cytochrome P-450. Mephenytoin p-hydroxylase and sparteine monooxygenase. Drug Metab Dispos. 1985 Jul-Aug;13(4):443–448. [PubMed] [Google Scholar]
  16. Inaba T., Nakano M., Otton S. V., Mahon W. A., Kalow W. A human cytochrome P-450 characterized by inhibition studies as the sparteine-debrisoquine monooxygenase. Can J Physiol Pharmacol. 1984 Jul;62(7):860–862. doi: 10.1139/y84-144. [DOI] [PubMed] [Google Scholar]
  17. Inaba T., Tyndale R. E., Mahon W. A. Quinidine: potent inhibition of sparteine and debrisoquine oxidation in vivo. Br J Clin Pharmacol. 1986 Aug;22(2):199–200. doi: 10.1111/j.1365-2125.1986.tb05251.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Leemann T., Dayer P., Meyer U. A. Single-dose quinidine treatment inhibits metoprolol oxidation in extensive metabolizers. Eur J Clin Pharmacol. 1986;29(6):739–741. doi: 10.1007/BF00615971. [DOI] [PubMed] [Google Scholar]
  19. Mahgoub A., Idle J. R., Dring L. G., Lancaster R., Smith R. L. Polymorphic hydroxylation of Debrisoquine in man. Lancet. 1977 Sep 17;2(8038):584–586. doi: 10.1016/s0140-6736(77)91430-1. [DOI] [PubMed] [Google Scholar]
  20. Mahon W. A., Mayersohn M., Inaba T. Disposition kinetics of two oral forms of quinidine. Clin Pharmacol Ther. 1976 May;19(5 Pt 1):566–575. doi: 10.1002/cpt1976195part1566. [DOI] [PubMed] [Google Scholar]
  21. Mikus G., Ha H. R., Vozeh S., Zekorn C., Follath F., Eichelbaum M. Pharmacokinetics and metabolism of quinidine in extensive and poor metabolisers of sparteine. Eur J Clin Pharmacol. 1986;31(1):69–72. doi: 10.1007/BF00870989. [DOI] [PubMed] [Google Scholar]
  22. Ochs H. R., Greenblatt D. J., Woo E. Clinical pharmacokinetics of quinidine. Clin Pharmacokinet. 1980 Mar-Apr;5(2):150–168. doi: 10.2165/00003088-198005020-00003. [DOI] [PubMed] [Google Scholar]
  23. Otton S. V., Brinn R. U., Gram L. F. In vitro evidence against the oxidation of quinidine by the sparteine/debrisoquine monooxygenase of human liver. Drug Metab Dispos. 1988 Jan-Feb;16(1):15–17. [PubMed] [Google Scholar]
  24. Otton S. V., Inaba T., Kalow W. Competitive inhibition of sparteine oxidation in human liver by beta-adrenoceptor antagonists and other cardiovascular drugs. Life Sci. 1984 Jan 2;34(1):73–80. doi: 10.1016/0024-3205(84)90332-1. [DOI] [PubMed] [Google Scholar]
  25. Otton S. V., Inaba T., Kalow W. Inhibition of sparteine oxidation in human liver by tricyclic antidepressants and other drugs. Life Sci. 1983 Feb 14;32(7):795–800. doi: 10.1016/0024-3205(83)90315-6. [DOI] [PubMed] [Google Scholar]
  26. Speirs C. J., Murray S., Boobis A. R., Seddon C. E., Davies D. S. Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine. Br J Clin Pharmacol. 1986 Dec;22(6):739–743. doi: 10.1111/j.1365-2125.1986.tb02969.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Steiner E., Dumont E., Spina E., Dahlqvist R. Inhibition of desipramine 2-hydroxylation by quinidine and quinine. Clin Pharmacol Ther. 1988 May;43(5):577–581. doi: 10.1038/clpt.1988.76. [DOI] [PubMed] [Google Scholar]
  28. Vinks A., Inaba T., Otton S. V., Kalow W. Sparteine metabolism in Canadian Caucasians. Clin Pharmacol Ther. 1982 Jan;31(1):23–29. doi: 10.1038/clpt.1982.4. [DOI] [PubMed] [Google Scholar]
  29. Zanger U. M., Vilbois F., Hardwick J. P., Meyer U. A. Absence of hepatic cytochrome P450bufI causes genetically deficient debrisoquine oxidation in man. Biochemistry. 1988 Jul 26;27(15):5447–5454. doi: 10.1021/bi00415a010. [DOI] [PubMed] [Google Scholar]

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