Journal
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY
Volume 104, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pnpbp.2020.110042
Keywords
ABCB1; ABCG2; CYP2D6; Pharmacogenetics; Long-acting risperidone
Funding
- Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project Experimental and clinical research of hypoxic-ischemic damage in perinatal and adult brain - European Union through the European Regional Development Fund) [KK01.1.1.01.0007]
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The study investigated the relationship between ABC gene polymorphisms and CYP genotypes in the context of long-acting risperidone treatment. It found that the impact of CYP2D6 genotype on risperidone exposure was dependent on the ABCG2 421C > A polymorphism, while ABC gene polymorphisms affected clinical response independently of systemic risperidone disposition.
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 > 7) 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.
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