ABCB1, ABCG2 and CYP2D6 polymorphism effects on disposition and response to long-acting risperidone.
Prog Neuropsychopharmacol Biol Psychiatry
; 104: 110042, 2021 01 10.
Article
in En
| MEDLINE
| ID: mdl-32682874
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Schizophrenia
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Antipsychotic Agents
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Risperidone
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Cytochrome P-450 CYP2D6
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ATP Binding Cassette Transporter, Subfamily G, Member 2
Type of study:
Observational_studies
/
Prognostic_studies
Limits:
Adult
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Aged
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Female
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Humans
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Male
/
Middle aged
Language:
En
Journal:
Prog Neuropsychopharmacol Biol Psychiatry
Year:
2021
Document type:
Article
Affiliation country: