engleski

Interplay of CYP2D6, ABCB1 and ABCG2 polymorphisms - effect on exposure, efficacy and safety of long-acting risperidone in schizophrenia patients

BACKGROUND-AIM. Risperidone (RIS) and its active metabolite 9-hydroxyrisperidone (9- OHRIS) are metabolised by enzymes CYP2D6 and CYP3A, and both are substrates of drug transporters ABCB1 and ABCG2. Aim of the study was to investigate the effect of genetic variations of metabolic enzymes and drug transporters on long-acting risperidone (RIS- LAI) treatment. METHODS. The study included 101 schizophrenia patient treated with RIS-LAI (25, 37.5, or 50 mg). Genotyping of ABCB1 (1236C>T, 2677G>T/A, 3435C>T), ABCG2 421C>A, CYP2D6 (dupl, *3, *4, *5, *6, *41), CYP3A4*22, CYP3A5*3 was performed by TaqMan real-time PCR or long-range PCR. Serum steady-state concentrations of RIS and 9- OHRIS were measured by HPLC-DAD on the 5th and 14th day following RIS-LAI injection. Efficacy was assessed by PANNS and extrapyramidal symptoms (EPS) by Simpson-Angus Scale (SAS). RESULTS. CYP2D6 EM/UM phenotype was independently associated with lower dose- corrected concentrations (c/d) of RIS (GMR=0.67, 95%CI 0.52-0.86 ; P=0.002) and 9- OHRIS (0.76, 0.61-0.95 ; P=0.015), and RIS/9- OHRIS ratio (0.80, 0.69-0.92 ; P=0.002). ABCG2 421C>A variant allele carriage was independently associated with lower c/d RIS+9- OHRIS (0.75, 0.56-0.99 ; P=0.046). The effect of ABCG2 variant allele on RIS+9-OHRIS levels in CYP2D6 EM/UM subjects appeared more pronounced than in overall cohort (0.60, 0.42-0.85 vs. 0.75, 0.56-0.99), with no effect in other CYP2D6 phenotypes (1.11, 0.69-1.80). It was also associated with lower RIS (0.66 ; 0.44-0.98) and 9-OHRIS (0.64 ; 0.45-0.90) levels. The effect of ABCG2 variant allele on c/d RIS+9-OHRIS levels in ABCB1 CC/GG/CC carriers was more pronounced than in overall cohort (0.52, 0.31- 0.88 vs. 0.75, 0.56-0.99). The use of mood stabilizers was associated with the EPS (GMR=2.14, 95%CI 1.05-4.35 ; P=0.036), and the odds for use of antim uscarinics (7.31, 1.10- 48.5 ; P=0.039). CONCLUSION. CYP2D6 phenotype and ABCG2 genotype had a significant influence on RIS-LAI exposure. The effect of CYP2D6 EM/UM and ABCB1 CC/GG/CC on lower c/d RIS, 9-OHRIS and RIS+9-OHRIS levels was more pronounced in ABCG2 421C>A variant carriers. This study points out for the first time importance of interaction between CYP2D6, ABCB1 with ABCG2 in risperidone treatment. Concomitant use of other drugs was relevant for RIS-LAI safety.

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

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