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

Autori
Ganoci, Lana ; Trkulja, Vladimir ; Živković, Maja ; Božina, Tamara ; Šagud, Marina ; Lovrić, Mila ; Božina, Nada

Izvornik
Progress in neuro-psychopharmacology & biological psychiatry (0278-5846) 104 (2021); 110042, 10

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
ABCB1 ; ABCG2 ; CYP2D6 ; pharmacogenetics ; long-acting risperidone

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

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