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. 1995 Apr;39(4):417–420. doi: 10.1111/j.1365-2125.1995.tb04471.x

Cytochrome P4502D6 genotype does not determine response to clozapine.

M J Arranz 1, E Dawson 1, S Shaikh 1, P Sham 1, T Sharma 1, K Aitchison 1, M A Crocq 1, M Gill 1, R Kerwin 1, D A Collier 1
PMCID: PMC1365130  PMID: 7640149

Abstract

1. The atypical antipsychotic drug clozapine, used in the treatment of resistant schizophrenia, is metabolized partly by the hepatic cytochrome P450 enzyme CYP2D6. Two phenotypes with respect to the activity of the enzyme are recognized (extensive metabolisers (EM) and poor metabolisers (PM)), resulting from allelic variation in the gene, CYP2D6. 2. Genotype was determined in 123 schizophrenic patients currently being treated with clozapine, in order to determine if EM or PM status influences response to this drug. Patients were divided into responders and non-responders using the Global Assessment Scale, and genotyped for the A and B poor metaboliser mutations by digesting PCR products with HpaII or BstNI. 3. Fifty-nine patients were heterozygous for allele B and for allele A. Eight patients were determined as poor metabolisers since they were homozygous either for A and B. Poor metabolisers were equally distributed between responders and nonresponders and no correlation between CYP2D6 alleles and response to clozapine was found. 4. The results are consistent with recent findings showing that CYP1A2, rather than CYP2D6, is the major enzyme responsible for the metabolism of clozapine.

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Selected References

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  1. Balant-Gorgia A. E., Gex-Fabry M., Balant L. P. Clinical pharmacokinetics of clomipramine. Clin Pharmacokinet. 1991 Jun;20(6):447–462. doi: 10.2165/00003088-199120060-00002. [DOI] [PubMed] [Google Scholar]
  2. Bertilsson L., Dahl M. L., Sjöqvist F., Aberg-Wistedt A., Humble M., Johansson I., Lundqvist E., Ingelman-Sundberg M. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet. 1993 Jan 2;341(8836):63–63. doi: 10.1016/0140-6736(93)92546-6. [DOI] [PubMed] [Google Scholar]
  3. Bertilsson L., Lou Y. Q., Du Y. L., Liu Y., Kuang T. Y., Liao X. M., Wang K. Y., Reviriego J., Iselius L., Sjöqvist F. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther. 1992 Apr;51(4):388–397. doi: 10.1038/clpt.1992.38. [DOI] [PubMed] [Google Scholar]
  4. Dahl M. L., Llerena A., Bondesson U., Lindström L., Bertilsson L. Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms. Br J Clin Pharmacol. 1994 Jan;37(1):71–74. doi: 10.1111/j.1365-2125.1994.tb04242.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Endicott J., Spitzer R. L., Fleiss J. L., Cohen J. The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry. 1976 Jun;33(6):766–771. doi: 10.1001/archpsyc.1976.01770060086012. [DOI] [PubMed] [Google Scholar]
  6. Evans W. E., Relling M. V., Rahman A., McLeod H. L., Scott E. P., Lin J. S. Genetic basis for a lower prevalence of deficient CYP2D6 oxidative drug metabolism phenotypes in black Americans. J Clin Invest. 1993 May;91(5):2150–2154. doi: 10.1172/JCI116441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Farde L., Wiesel F. A., Halldin C., Sedvall G. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry. 1988 Jan;45(1):71–76. doi: 10.1001/archpsyc.1988.01800250087012. [DOI] [PubMed] [Google Scholar]
  8. Fischer V., Vogels B., Maurer G., Tynes R. E. The antipsychotic clozapine is metabolized by the polymorphic human microsomal and recombinant cytochrome P450 2D6. J Pharmacol Exp Ther. 1992 Mar;260(3):1355–1360. [PubMed] [Google Scholar]
  9. Gaedigk A., Blum M., Gaedigk R., Eichelbaum M., Meyer U. A. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am J Hum Genet. 1991 May;48(5):943–950. [PMC free article] [PubMed] [Google Scholar]
  10. Gauch R., Michaelis W. The metabolism of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e) (1,4)diazepine (clozapine) in mice, dogs and human subjects. Farmaco Prat. 1971 Nov;26(11):667–681. [PubMed] [Google Scholar]
  11. Gonzalez F. J. Human cytochromes P450: problems and prospects. Trends Pharmacol Sci. 1992 Sep;13(9):346–352. doi: 10.1016/0165-6147(92)90107-h. [DOI] [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. Gough A. C., Miles J. S., Spurr N. K., Moss J. E., Gaedigk A., Eichelbaum M., Wolf C. R. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature. 1990 Oct 25;347(6295):773–776. doi: 10.1038/347773a0. [DOI] [PubMed] [Google Scholar]
  14. Hanioka N., Kimura S., Meyer U. A., Gonzalez F. J. The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934----A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3' splice recognition site. Am J Hum Genet. 1990 Dec;47(6):994–1001. [PMC free article] [PubMed] [Google Scholar]
  15. Jerling M., Lindström L., Bondesson U., Bertilsson L. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit. 1994 Aug;16(4):368–374. doi: 10.1097/00007691-199408000-00006. [DOI] [PubMed] [Google Scholar]
  16. Kahn R. S., Davidson M., Siever L., Gabriel S., Apter S., Davis K. L. Serotonin function and treatment response to clozapine in schizophrenic patients. Am J Psychiatry. 1993 Sep;150(9):1337–1342. doi: 10.1176/ajp.150.9.1337. [DOI] [PubMed] [Google Scholar]
  17. Kerwin R. W. The new atypical antipsychotics. A lack of extrapyramidal side-effects and new routes in schizophrenia research. Br J Psychiatry. 1994 Feb;164(2):141–148. doi: 10.1192/bjp.164.2.141. [DOI] [PubMed] [Google Scholar]
  18. Kimura S., Umeno M., Skoda R. C., Meyer U. A., Gonzalez F. J. The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet. 1989 Dec;45(6):889–904. [PMC free article] [PubMed] [Google Scholar]
  19. Meltzer H. Y. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 1989;99 (Suppl):S18–S27. doi: 10.1007/BF00442554. [DOI] [PubMed] [Google Scholar]
  20. Shaikh S., Collier D., Kerwin R. W., Pilowsky L. S., Gill M., Xu W. M., Thornton A. Dopamine D4 receptor subtypes and response to clozapine. Lancet. 1993 Jan 9;341(8837):116–116. doi: 10.1016/0140-6736(93)92594-j. [DOI] [PubMed] [Google Scholar]
  21. Smith C. A., Gough A. C., Leigh P. N., Summers B. A., Harding A. E., Maraganore D. M., Sturman S. G., Schapira A. H., Williams A. C., Maranganore D. M. Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease. Lancet. 1992 Jun 6;339(8806):1375–1377. doi: 10.1016/0140-6736(92)91196-f. [DOI] [PubMed] [Google Scholar]
  22. Stock B., Spiteller G., Heipertz R. Austausch aromatisch gebundenen Halogens gegen OH- und SCH3- bei der Metabolisierung des Clozapins im menchlichen Körper. Arzneimittelforschung. 1977;27(5):982–990. [PubMed] [Google Scholar]
  23. Vallada H., Collier D., Dawson E., Owen M., Nanko S., Murray R., Gill M. Debrisoquine 4-hydroxylase (CYP2D) locus and possible susceptibility to schizophrenia. Lancet. 1992 Jul 18;340(8812):181–182. doi: 10.1016/0140-6736(92)93266-p. [DOI] [PubMed] [Google Scholar]
  24. Van Tol H. H., Bunzow J. R., Guan H. C., Sunahara R. K., Seeman P., Niznik H. B., Civelli O. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature. 1991 Apr 18;350(6319):610–614. doi: 10.1038/350610a0. [DOI] [PubMed] [Google Scholar]
  25. Van Tol H. H., Wu C. M., Guan H. C., Ohara K., Bunzow J. R., Civelli O., Kennedy J., Seeman P., Niznik H. B., Jovanovic V. Multiple dopamine D4 receptor variants in the human population. Nature. 1992 Jul 9;358(6382):149–152. doi: 10.1038/358149a0. [DOI] [PubMed] [Google Scholar]

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