Uloga farmakogenetičkih varijacija u terapiji depresije [ The role of pharmacogenetic variations in the therapy of depression ]

Božina, Nada (2005) Uloga farmakogenetičkih varijacija u terapiji depresije [ The role of pharmacogenetic variations in the therapy of depression ]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Genetic variations of metabolic enzymes and transporter proteins are important determinants of pharmacotherapy efficacy and toxicity. In addition, interindividual, interethnic differences in the prevalence of genetic variations are signifficant. In this study, pharmacogenetic analysis was performed in Croatian healthy population and patients with depression. The influence of genetic variations of metabolic enzymes: CYP2C9, CYP2C19, CYP2D6, CYP3A4 and transporter proteins: P-glycoprotein (MDR1) and serotonin transporter (SERT) on pharmacologic and toxicologic effects of major depression therapy were investigated. The study included 286 healthy subjects and 114 patients with major depression. Pharmacogenetic analyses were performed by PCR-RFLP methods. Drug concentrations were determined by GC-MS and HPLC methods. The prevalence of allelic variants and predicted genotypes in the Croatian population ranged between values for Mid-European and Mediterranean populations. The prevalence of CYP2C19 genotype with mutant alleles was higher in population with major depression than in healthy population. Frequencies of homozygous “wild type” alleles of CYP2D6 were higher in healthy population, while homozygous mutant alleles were significantly higher in patients with major depression. Frequencies of ultraextensive CYP2D6 genotype were significantly higher in non-responder than in responder group. Significantly higher requencies of mutant CYP2D6 alleles were found in patients with adverse drug reactions compared to the group without adverse reactions. G2677 allele of MDR1 gene was more frequent in non-responder than in responder group. Frequencies of SERT-LL and SERT-ss genotypes were significantly higher in the group of patients without than in the group with adverse reactions. Variable paroxetine concentrations due to different CYP2D6 genotypes were more pronounced at the beginning of therapy, while differences in steady state were diminished. The results obtained could contribute to therapy individualization.

Abstract in Croatian

Genske varijacije metaboličkih enzima i transportnih proteina mogu biti važne odrednice učinkovitosti i toksičnosti farmakoterapije. Uz međuindividualne razlike značajne su i međuetničke razlike u učestalosti polimorfnih oblika gena. U ovoj smo studiji proveli farmakogenetičku analizu u hrvatskoj zdravoj populaciji i u bolesnika s depresijom te istražili utjecaj genskih varijacija metaboličkih enzima: CYP2C9, CYP2C19, CYP2D6, CYP3A4 i transportnih proteina: P-glikoproteina (MDR1) i serotoninskog trensportera (SERTR) na farmakološke i toksične učinke pri terapiji velikog depresivnog poremećaja. U ispitivanju je sudjelovalo 286 zdravih osoba i 114 bolesnika s velikim depresivnim poremećajem. Za farmakogenetičke analize korištena je metoda PCR RFLP. Učestalosti polimorfnih alela i genotipova bile su uglavnom između vrijednosti za srednjeeuropske i mediteranske bijele populacije. Učestalost genotipa CYP2C19 s mutiranim alelima bila je viša u populaciji bolesnika s velikim depresivnim poremećajem u odnosu na zdravu populaciju. U zdravoj populaciji značajno je više homozigota za wt-“divlji” tip alela gena CYP2D6 dok je u populaciji bolesnika s velikim depresivnim poremećajem bilo značajno više homozigotnih nosioca mutiranih alela. Učestalosti genotipa vrlo brzih metabolizatora CYP2D6 bila je značajno viša u skupini bolesnika koji su bili rezistentni na terapiju u odnosu na skupinu s dobrim odgovorom. Pronađena je značajno viša učestalost mutiranih alela CYP2D6 u skupini bolesnika s nuspojavama prema skupini bez nuspojava. Alel G2677 gena MDR1 češće je zastupljen u skupini bolesnika koja je bila rezistentna na terapiju u odnosu na skupinu sa učinkovitom terapijom Učestalost genotipova SERT-LL i SERT-ss bila je statistički značajno viša u bolesnika bez nuspojava u odnosu na skupinu s nuspojavama. Varijabilne interindividualne vrijednosti koncentracija paroksetina koje su rezultat varijabilnog genotipa CYP2D6 u populaciji izraženije su na početku terapije, dok su razlike u ravnoteži smanjene.Ovi rezultati predstavljaju doprinos suvremenom trendu individualizacije terapije.

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