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. 1986 Jul;22(1):89–92.

Inhibitory effects of neuroleptics on debrisoquine oxidation in man.

E K Syvälahti, R Lindberg, J Kallio, M De Vocht
PMCID: PMC1401082  PMID: 2874826

Abstract

Liver oxidative metabolism, assessed by debrisoquine hydroxylation test, was studied in 107 healthy volunteers and in 71 patients with or without neuroleptic drug treatment. The mean metabolic ratio (MR = debrisoquine/4-hydroxydebrisoquine excretion in the urine) was 2.8 +/- 0.1 (s.e. mean) in the control group, six persons being poor metabolizers of debrisoquine (MR greater than or equal to 12.6). The mean MR (12.1 +/- 1.5) was significantly higher in those 42 patients taking neuroleptics than in patients without neuroleptics (0.8 +/- 0.1). In the former group, seventeen patients had a MR exceeding 12.6. Oral contraceptives, antiepileptics, benzodiazepines and progestin derivates did not increase MR values, the highest individual ratio being 2.72 in those subjects not receiving neuroleptics. These results suggest a probable competitive inhibition of oxidative metabolism by neuroleptics. This is a phenomenon of potential clinical importance both in patients with an inherited poor metabolic capacity and in patients receiving other drugs like beta-adrenoceptor blocking agents and tricyclic antidepressants oxidized by the same enzyme system.

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Selected References

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

  1. Alvan G., von Bahr C., Seidemann P., Sjöqvist F. High plasma concentrations of beta-receptor blocking drugs and deficient debrisoquine hydroxylation. Lancet. 1982 Feb 6;1(8267):333–333. doi: 10.1016/s0140-6736(82)91583-5. [DOI] [PubMed] [Google Scholar]
  2. Bertilsson L., Dengler H. J., Eichelbaum M., Schulz H. U. Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine. Eur J Clin Pharmacol. 1980 Feb;17(2):153–155. doi: 10.1007/BF00562624. [DOI] [PubMed] [Google Scholar]
  3. Bertilsson L., Eichelbaum M., Mellström B., Säwe J., Schulz H. U., Sjöqvist F. Nortriptyline and antipyrine clearance in relation to debrisoquine hydroxylation in man. Life Sci. 1980 Nov 3;27(18):1673–1677. doi: 10.1016/0024-3205(80)90642-6. [DOI] [PubMed] [Google Scholar]
  4. Bertilsson L., Mellström B., Sjökvist F., Mårtenson B., Asberg M. Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implications. Lancet. 1981 Mar 7;1(8219):560–561. doi: 10.1016/s0140-6736(81)92894-4. [DOI] [PubMed] [Google Scholar]
  5. Eichelbaum M. Defective oxidation of drugs: pharmacokinetic and therapeutic implications. Clin Pharmacokinet. 1982 Jan-Feb;7(1):1–22. doi: 10.2165/00003088-198207010-00001. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. Hanssen T., Heyden T., Sundberg I., Alfredsson G., Nybäck H., Wetterberg L. Propranolol in schizophrenia. Clinical, metabolic, and pharmacological findings. Arch Gen Psychiatry. 1980 Jun;37(6):685–690. doi: 10.1001/archpsyc.1980.01780190083010. [DOI] [PubMed] [Google Scholar]
  9. Kahn G. C., Boobis A. R., Brodie M. J., Toverud E. L., Murray S., Davies D. S. Phenacetin O-deethylase: an activity of a cytochrome P-450 showing genetic linkage with that catalysing the 4-hydroxylation of debrisoquine? Br J Clin Pharmacol. 1985 Jul;20(1):67–76. doi: 10.1111/j.1365-2125.1985.tb02800.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lennard M. S., Silas J. H., Smith A. J., Tucker G. T. Determination of debrisoquine and its 4-hydroxy metabolite in biological fluids by gas chromatography with flame-ionization and nitrogen-selective detection. J Chromatogr. 1977 Mar 11;133(1):161–166. doi: 10.1016/s0021-9673(00)89216-x. [DOI] [PubMed] [Google Scholar]
  11. Linnoila M., George L., Guthrie S. Interaction between antidepressants and perphenazine in psychiatric inpatients. Am J Psychiatry. 1982 Oct;139(10):1329–1331. doi: 10.1176/ajp.139.10.1329. [DOI] [PubMed] [Google Scholar]
  12. Loga S., Curry S., Lader M. Interaction of chlorpromazine and nortriptyline in patients with schizophrenia. Clin Pharmacokinet. 1981 Nov-Dec;6(6):454–462. doi: 10.2165/00003088-198106060-00003. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Nelson J. C., Jatlow P. I. Neuroloeptic effect on desipramine steady-state plasma concentratins. Am J Psychiatry. 1980 Oct;137(10):1232–1234. doi: 10.1176/ajp.137.10.1232. [DOI] [PubMed] [Google Scholar]
  15. Oates N. S., Shah R. R., Idle J. R., Smith R. L. Genetic polymorphism of phenformin 4-hydroxylation. Clin Pharmacol Ther. 1982 Jul;32(1):81–89. doi: 10.1038/clpt.1982.130. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Peet M., Middlemiss D. N., Yates R. A. Pharmacokinetic interaction between propranolol and chlorpromazine in schizophrenic patients. Lancet. 1980 Nov 1;2(8201):978–978. doi: 10.1016/s0140-6736(80)92135-2. [DOI] [PubMed] [Google Scholar]
  18. Ritchie J. C., Sloan T. P., Idle J. R., Smith R. L. Toxicological implications of polymorphic drug metabolism. Ciba Found Symp. 1980;76:219–244. doi: 10.1002/9780470720592.ch12. [DOI] [PubMed] [Google Scholar]
  19. Sloan T. P., Mahgoub A., Lancaster R., Idle J. R., Smith R. L. Polymorphism of carbon oxidation of drugs and clinical implications. Br Med J. 1978 Sep 2;2(6138):655–657. doi: 10.1136/bmj.2.6138.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Spina E., Birgersson C., von Bahr C., Ericsson O., Mellström B., Steiner E., Sjöqvist F. Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes. Clin Pharmacol Ther. 1984 Nov;36(5):677–682. doi: 10.1038/clpt.1984.239. [DOI] [PubMed] [Google Scholar]
  21. Vestal R. E., Kornhauser D. M., Hollifield J. W., Shand D. G. Inhibition of propranolol metabolism by chlorpromazine. Clin Pharmacol Ther. 1979 Jan;25(1):19–24. doi: 10.1002/cpt197925119. [DOI] [PubMed] [Google Scholar]
  22. von Bahr C., Spina E., Birgersson C., Ericsson O., Göransson M., Henthorn T., Sjöqvist F. Inhibition of desmethylimipramine 2-hydroxylation by drugs in human liver microsomes. Biochem Pharmacol. 1985 Jul 15;34(14):2501–2505. doi: 10.1016/0006-2952(85)90533-7. [DOI] [PubMed] [Google Scholar]

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