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Influence of CYP2D6 and ABCB1 polimorphisms on the serum steady-state concentrations of risperidone and 9-oh risperidone in patients using long-acting injectable risperidone

INTRODUCTION: An increased risk of adverse effects and discontinuation of risperidone therapy is observed in patients with schizophrenia. Long-acting injectable (LAI) risperidone should have improved pharmacokinetics and reduce side effects. Risperidone is metabolized to its active metabolite, 9-OH risperidone, mainly by CYP2D6. Both risperidone and 9-OH risperidone are substrates of P- glycoprotein (ABCB1). AIM: The aim of this study is to investigate the role of genetic variations of CYP2D6 and ABCB1 on serum steady-state concentrations of risperidone and 9-OH risperidone in patients using LAI risperidone. MATERIALS AND METHODS: The study included 42 schizophrenic patients treated with 25, 37.5 and 50 mg of LAI risperidone. Pharmacogenetic analysis were performed by real-time PCR analysis for genotyping of CYP2D6 *3, *4, *6, ABCB1 C1236T, G2677T/A and C3435T variants. CYP2D6*5 and duplications were genotyped by long-distance PCR. Serum steady-state concentrations of risperidone and 9-OH risperidone were measured on 5th and 13th day following risperidone injection by high-performance liquid chromatography with diode array detection (HPLC-DAD). RESULTS: The median active moiety concentrations were on 5th day 76.5 nmol/L (95%CI=56.4-102.6), and on 13th day 41.2 nmol/L (95%CI=30.1-49.7). On 13th day concentrations and concentration/dose (C/D) ratios of risperidone, 9-OH risperidone and active moiety were significantly lower (p=0.0005, p<0.0001 and p<0.0001 respectively). The active moiety concentrations on 13th day were significantly different according to CYP2D6 genotype (p=0.0455). The median active moiety concentration for ultrarapid CYP2D6 metabolizers on 5th day was 26.8 nmol/L and on 13th day 31.1 nmol/L. The median active moiety concentration on 13th day for extensive CYP2D6 metabolizers was 31.2 nmol/L (95%CI=25.4-48.6), and for intermediate and poor CYP2D6 metabolizers was 48.7 nmol/L (95%CI=30.3-78.8). No significant difference was found in concentrations and C/D ratios of risperidone, 9-OH risperidone and active moiety according to ABCB1 genotypes. CONCLUSIONS: The CYP2D6 genotypes had a strong influence on the steady-state serum levels of risperidone, 9-OH risperidone and active moiety. The active moiety concentrations for ultrarapid CYP2D6 metabolizers on 5th and 13th day were bellow recommended therapeutic range (50-150 nmol/L). The active moiety concentrations on 13th day were bellow recommended therapeutic range (50-150 nmol/L). Results pointed to unacceptable interindividual differences in LAI risperidone concentrations.

long-acting injectable risperidone; CYP2D6; ABCB1; polimorphisms; pharmacokinetics; pharmacogenetics

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