GENETSKI POLIMORFIZEM CYP2D6 IN EKSTRAPIRAMIDNI STRANSKI UČINKI ANTIPSIHOTIČNIH ZDRAVIL
Ključne besede:
shizofrenija, antipsihotiki, ekstrapiramidni stranski učinki, genetski polimorfizem, CYP2D6, genotip, fenotip, farmakogenetikaPovzetek
Izhodišča. Antipsihotična zdravila ter nekatera druga psihiatrična in nepsihiatrična zdravila povzročajo ekstrapiramidne simptome. Nekateri izmed njih, npr. tardivne diskinezije, so lahko ireverzibilni in pomembno vplivajo na kakovost življenja posameznikov. V njihovo etiopatogenezo so vključeni različni dejavniki. Avtorici v članku predstavljata genetski polimorfizem izoencima CYP2D6 in njegovo morebitno povezanost z nastankom ekstrapiramidnih simptomov, saj se prek izoencima CYP2D6 metabolizira večina antipsihotičnih zdravil. Predstavljene so metode fenotipizacije in genotipizacije CYP2D6, povezave med genotipom in fenotipom ter pregled nekaterih kliničnih študij, ki bodisi potrjujejo ali pa zanikajo vlogo genetskega polimorfizma v nastanku ekstrapiramidnih stranskih učinkov antipsihotičnih zdravil.
Zaključki. Genotip ali fenotip CYP2D6 izoencima morda res še nimata natančno postavljene vloge v pojavnosti ekstrapiramidnih stranskih učinkov antipsihotičnih zdravil, nedvomno pa njuno poznavanje lahko pomaga pri ločitvi bolnikov, ki imajo terapevtske probleme zaradi spremenjene presnove zdravil, ki so substrati za CYP2D6, od tistih, ki imajo terapevtske probleme zaradi drugih mehanizmov delovanja zdravil. Farmakogenetika tudi na ta način vse pomembneje vstopa v vsakodnevno uporabo zdravil.
Prenosi
Literatura
Vandel P, Haffen E, Vandel S et al. Drug extrapyramidal side effects. CYP2D6 genotypes and phenotypes. Eur J Clin Pharmacol 1999; 55: 659–65.
Vandel P, Bonin B, Leveque E, Sechter D, Bizouard P. Tricyclic antidepressant-induced extrapyramidal side effects. Eur Neuropharmacol 1997; 7: 207–12.
Yassa R, Camille Y, Belzile L. Tardive dyskinesia in the course of antidepressant therapy: a prevalence study and review of the literature. J Clin Psychopharmacol 1987; 7: 243–6.
Gerver PE, Lynd LD. Selective serotonin-reuptake inhibitor-induced movement disorders. Ann Pharmacother 1998; 32: 692–8.
Cunningham Owens DG. A guide to the extrapyramidal side-effects of antipsychotic drugs. Cambridge: University Press; 1999.
Scordo MG, Spina E, Romeo P et al. CYP2D6 genotype and antipsychoticinduced extrapyramidal side effects in schizophrenic patients. Eur J Clin Pharmacol 2000; 56: 679–83.
Casey DE. Motor and mental aspects of extrapyramidal syndromes. Int Clin Psychopharmacol 1995; 10: Suppl 3: 105–14.
Morgenstern H, Glazer WH. Identifying risk factors for tardive dyskinesia among long-term outpatients maintained with neuroleptic medications. Arch Gen Psychiatry 1993; 50: 723–33.
Chakos MH, Alvir JMJ, Woerner MG et al. Incidence and correlates of tardive dyskinesia in first episode of schizophrenia. Arch Gen Psychiatry 1996; 53: 313–9.
Saltz B, Woerner MG, Kane JM et al. Prospective study of tardive dyskinesia incidence in the elderly. JAMA 1991; 266: 2402–6.
Andreassen OA, MacEwan T, Gulbrandsen AK, McCreadie RG, Steen VM. Non-functional CYP2D6 alleles and risk for neuroleptic-induced movement disorders in schizophrenic patients. Psychopharmacology 1997; 131: 174–9.
Reggiani K, Vandel P, Haffen E et al. Extrapyramidal side effects of neuroleptic and antidepressant treatment: assessment of potential risk factors through CYP2D6 genetic polymorphism. Encephale 2000; 26: 62–7.
Dahl ML, Ekqvist B, Widen J, Bertilsson L. Disposition of the neuroleptic zuclopenthixol cosegregates with the polymorphic hydroxilation of debrisoquine in humans. Acta Psychiatr Scand 1991; 84: 99–100.
Otani K, Aoshima T. Pharmacogenetics of classical and new antipsychotic drugs. Ther Drug Monit 2000; 22: 118–21.
Sproule BA, Naranjo CA, Brenner KE, Hassan PC. Selective serotonin reuptake inhibits and CNS drug interactions: critical review of the evidence. Clin Pharmacokinet 1997; 33: 454–71.
Nemeroff CB, DeVane CL, Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996; 153: 311–20.
Kudo S, Ishizaki T. Pharmacokinetics of halperidol: an update. Clin Pharmacokinet 1999; 37: 435–56.
Siegle I, Fritz P, Eckhardt K, Zanger UM, Eichelbaum M. Cellular localization and regional distribution of CYP2D6 mRNA and protein expression in human brain. Pharmacogenetics 2001; 11: 237–45.
Idle JR, Corchero J, Gonzales FJ. Medical implications of HGP’s sequence on chromosome 22. Lancet 2000; 355: 319–9.
Llerena A, Herraiz AG, Cobaleda J, Johansson I, Dahl ML. Debrisoquin and mephenytoin hydroxylation phenotypes and CYP2D6 genotype in patients treated with neuroleptic and antidepressant agents. Clin Pharmacol Ther 1993; 54: 606–11.
Gough AC, Miles JS, Spurr NK et al. Identification of primary gene defect at the cytochrome P450 CYP2D6 locus. Nature 1990; 347: 773–5.
Wennerholm A, Johansson I, Massele AY et al. Decreased capacity for debrisoquine metabolism among black Tanzanians: analyses of the CYP2D6 genotype and phenotype. Pharmacogenetics 1999; 9: 365–70.
Lundquist E, Johansson I, Ingelman-Sundberg M. Genetic mechanisms for duplication and multiduplication of the human CYP2D6 gene and methods for detection of duplicated CYP2D6 genes. Gene 1999; 226: 327–38.
Breskvar K, Dolžan V, Lenasi H, Rudolf Z, Hudnik-Plevnik T. Analiza polimorfizma citokroma P-450 (CYPIID6), ki metabolizira ksenobiotike pri človeku. Zdrav Vestn 1994; 63: 213–5.
Dolžan V, Rudolf Z, Breskvar K. Human CYP2D6 gene polymorphism in Slovenian cancer patients and healthy controls. Carcinogenesis 1995; 16: 2675–8.
Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation: current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin Pharmacokinet 1995; 29: 192–209.
Raimundo S, Fischer J, Eichelbaum M, Griese EU, Schwab M, Zanger UM. Elucidation of the genetic basis of the common ‘intermediate metaboliser’ phenotype for the drug oxidation by CYP2D6. Pharmacogenetics 2000; 10: 1–5.
Bertilsson L, Dahk ML, Sjokvist F et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 1993; 341: 63–3.
Sachse C, Brockmoller J, Bauer S, Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1999: 60: 284–95.
Gaedigk A. Interethnic differences of drug-metabolizing enzymes. Intl J Clin Pharmacol Ther 2000; 38: 61–8.
Bork JA, Rogers T, Wedlund PJ, de Leon J. A pilot study on risperidone metabolism: the role of cytochromes P450 and 3A. J Clin Psychiatry 1999; 60: 469–76.
Pan L, Van der Stichele R, Rosseel MT et al. Effects of smoking, CYP2D6 genotype and concomitant drug intake on the steady state plasma concentrations of haloperidol and reduced haloperidol in schizophrenic inpatients. Drug Monit 1999; 21: 489–97.
Fang J, Baker GB, Silverstone PH et al. Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol. Cellular Molec Neurobiol 1997; 17: 227–33.
Pan LP, de Vriendt C, Belpaire FM. In-vitro characterisation of the cytochrome P450 isoenzymes involved in the back oxidation and N-dealkylation of reduced haloperidol. Pharmacogenetics 1998; 8: 383–9.
Tyndale R, Kalow W, Inaba T. Oxidation of reduced haloperidol to haloperidol: involvement of human P450IID6 (sparteine/debrisoquine monooxygenase). Br J Clin Pharmacol 1991; 31: 655–60.
Roh HK, Chung JJ, Oh DJ et al. Plasma concentrations of haloperidol and its reduced metabolite are related to the CYP2D6 genotype at low, but not hogh doses of haloperidol in Korean schizophrenic patients (in print).
Nyberg S, Farde L, Halldin C et al. D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate. Am J Psychiatry 1995; 152: 173–8.
Llerena A, Berecz R, de la Rubia A, Norberto MJ, Benitez J. Use of the mesoridazine/thioridazine ratio as a marker for CYP2D6 enzyme activity. Ther Drug Monit 2000; 22: 397–401.
Jerling M, Dahl ML, Aberg-Wistedt et al. The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol. Clin Pharmacol Ther 1996; 59: 423–8.
Kapitany T, Meszaros K, Lenzinger E et al. Genetic polymorphisms for drug metabolism (CYP2D6) and tardive dyskinesia in schizophrenia. Schizophr Res 1998; 32: 101–6.
Ellingrod VL, Schultz SK, Arndt S. Association between cytochrome P4502D6 (CYP2D6) genotype, antipsychotic exposure, and abnormal involuntary movements scale (AIMS) score. Psychiatr Genet 2000; 10: 9–11.
Arthur H, Dahl ML, Siwers B, Sjoqvist F. Polymorphic drug metabolism in schizophrenic patients with tardive dyskinesia. J Clin Psychopharmacol 1995; 15: 211–6.
Armstrong M, Daly AK, Blennerhassett R, Ferrier N, Idle JR. Antipsychotic drug-induced movement disorders in schizophrenia in relation to CYP2D6 genotype. Br J Psychiatry 1997; 170: 23–6.
Iwahashi K, Yoshihara E, Nakamura K et al. CYP2D6 HhaI genotype and the neuroleptic malignant syndrome. Neuropsychobiology 1999; 39: 33–7.
Ueno S, Otani K, Kaneko S et al. Cytochrome P-450 2D6 gene polymorphism is not associated with neuroleptic malignant syndrome. Biol Psychiatry 1996; 40: 72–4.
Aitchison KJ, Munro J, Wright P et al. Failure to respond to treatment with typical antipsychotics is not associated with CYP2D6 ultrarapid hydroxylation. Br J Clin Pharmacol 1999; 48: 388–94.
Pollock BG, Mulsant BH, Sweet RA. Prospective cytochrome P450 genotyping for neuroleptic treatment in dementia. Psychopharmacol Bull 1995; 31: 327–31.
Otani K, Aoshima T. Pharmacogenetics of classical and new antipsychotic drugs. Ther Drug Monit 2000; 22: 118–21.
Hamelin BA, Dorson PG, Pabis D et al. CYP2D6 mutations and therapeutic outcome in schizophrenia patients. Pharmacotherapy 1999; 19: 1057–63.
Vallada H, Collier D, Dawson E et al. Debrisoquine 4-hydroxylase (CYP2D6) locus and possible susceptibility to schizophrenia. Lancet 1992; 340: 181–2.
Spina E, Sturiale V, Valvo S et al. Debrisoquine oxidation phenotype and neuroleptic-induced dystonic reactions. Acta Psychiatr Scand 1992; 86: 364–6.
Chou WP, Yan FX, de Leon J et al. Extension of a pilot study: impact from the cytochrome 2D6 polymorphism on outcome and costs associated with severe mental illness. J Clin Psychopharmacol 2000; 20: 246–51.
Prenosi
Številka
Rubrika
Licenca
Avtor na prispevku, ki ga bo pripravil za Zdravniški vestnik, po pogodbi nanj prenaša vse materialne avtorske pravice, kakor izhajajo iz 22. člena Zakona o avtorski in sorodnih pravicah, in sicer pravico reproduciranja, pravico javnega izvajanja, pravico javnega prenašanja, pravico javnega predvajanja s fonogrami in videogrami, pravico javnega prikazovanja, pravico radiodifuznega oddajanja, pravico radiodifuzne retransmisije, pravico sekundarnega radiodifuznega oddajanja, pravico dajanja na voljo javnosti, pravico predelave, pravico avdiovizualne priredbe, pravico distribuiranja ter pravico dajanja v najem in vse druge pravice avtorja v skladu z ZASP.
Avtorjev prenos pravic po pogodbi je neizključen, velja za neomejeno število izdaj, za ves čas trajanja materialnih avtorskih pravic ter je prostorsko neomejen.
Avtor sme avtorsko delo tudi sam izkoriščati ali avtorske pravice prenašati na tretje osebe, vendar oboje šele po preteku 3 mesecev od prve objave dela v reviji Zdravniški vestnik.
Avtor Zdravniškemu vestniku izrecno dovoli, da lahko pravice, pridobljene v skladu s pogodbo prenaša naprej na tretje osebe brez omejitev.
Avtor se strinja, da Zdravniški vestnik prispevek objavi pod pogoji licence Creative Commons BY-NC 4.0 (navedba avtorstva-nekomercialno) ali primerljive licence.
