ABCB1, ABCG2 and CYP2D6 polymorphism effects on disposition and response to long-acting risperidone

Znanstveni rad - Izvorni znanstveni rad

• Autor: Lana Ganoci
• Autor: Vladimir Trkulja
• Autor: Maja Živković
• Autor: Tamara Božina
• Autor: Marina Šagud
• Autor: Mila Lovrić
• Autor: Nada Božina
• Autorova ustanova: Sveučilište u Zagrebu; Medicinski fakultet; (KATEDRA ZA TEMELJNU I KLINIČKU FARMAKOLOGIJU)
• Autorova ustanova: Sveučilište u Zagrebu; Medicinski fakultet; (KATEDRA ZA PSIHIJATRIJU I PSIHOLOŠKU MEDICINU)
• Znanstveno / umjetničko područje, polje i grana: BIOMEDICINA I ZDRAVSTVO; Kliničke medicinske znanosti; Psihijatrija
• Znanstveno / umjetničko područje, polje i grana: BIOMEDICINA I ZDRAVSTVO; Temeljne medicinske znanosti; Farmakologija

Sažetak (engleski)

The relevance of the multidrug resistance (ABCB1) and breast cancer resistance (ABCG2) protein transporter polymorphisms for treatment with long-acting intramuscular (LAI) risperidone is largely unknown. We explored the relationship between these polymorphisms and cytochrome P450 (CYP) 2D6 genotype-predicted phenotype in their effects on drug disposition and clinical outcomes in adults with schizophrenia. In a 24-week observational study, patients initiated on LAI-risperidone (n=101) were genotyped [enzymes (CYP2D6 dupl,*3,*4,*5,*6,*41; CYP3A4*22, CYP3A5*3), transporters (ABCG2 421C>A; ABCB1 1236C>T, 2677G>T/A, 3435C>T)] and evaluated for steady-state (weeks 6-8) serum levels of dose-corrected risperidone, 9-OH-risperidone, risperidone+9-OH-risperidone (active moiety), and for response to treatment (PANSS, reduction vs. baseline ≥30% at week 12 and ≥45% at week 24). CYP2D6 normal/ultrarapid metabolizers (NM/UM) (vs. other) had lower risperidone (29%) and active moiety levels (24%) (9-OH-risperidone not affected). The effect on the three analytes was mild (0 to 23% reduction) in ABCG2 wild-type homozygotes and pronounced (44-55% reduction) in ABCG2 variant allele carriers. ABCG2 variant had no effect on disposition in CYP2D6 "other" phenotypes, while the effect was pronounced in CYP2D6 NM/UM subjects (31-37% reduction). ABCB1 polymorphisms had no effect on exposure to risperidone. CYP2D6 NM/UM phenotype tended to lower odds of PANSS response, ABCG2 variant was associated with 4-fold higher odds and ABCB1 (1236C>T, 2677G>T/A, 3435C>T) overall mainly wild-type genotype was associated with around 4--fold lower odds of response. In patients treated with LAI-risperidone, CYP2D6 phenotype effect on systemic exposure is conditional on the ABCG2 421C>A polymorphism. ABCG2 and ABCB1 polymorphisms affect clinical response independently of systemic risperidone disposition.

• Ključne riječi (engleski): ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*; ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics*; Adult; Aged; Alleles; Antipsychotic Agents / therapeutic use*; Cytochrome P-450 CYP2D6 / genetics*; Female; Genotype; Humans; Male; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Risperidone / therapeutic use*; Schizophrenia / drug therapy*; Schizophrenia / genetics; Treatment Outcome; Young Adult
• Jezik: engleski
• Vrsta publikacije: Znanstveni rad - Izvorni znanstveni rad
• Status objave: Objavljen
• Vrsta recenzije: Recenziran
• Verzija publikacije: Završna verzija rukopisa prihvaćena za objavljivanje (postprint)
• Naslov časopisa: Progress in Neuro-Psychopharmacology and Biological Psychiatry
• Brojčani podaci: vol. 104, 110042
• p-ISSN: 0278-5846
• e-ISSN: 1878-4216
• DOI: https://doi.org/10.1016/j.pnpbp.2020.110042
• URN:NBN: urn:nbn:hr:105:975683
• Datum objave publikacije: 2021-01-10
• URL dokumenta: https://linkinghub.elsevier.com/retrieve/pii/S0278584620303584
• Vrsta resursa: Tekst
• Prava pristupa: Otvoreni pristup
• Datum i vrijeme pohrane: 2022-02-04 09:29:16