Evaluation of Correlation Between the Pharmacogenetic Profiles of Risperidone Treated Psychiatry Patients with Plasma and Urine Concentration of Risperidone and its Active Moiety 9-OH Risperidone Determined with Optimized Bioanalytical LC Method

Abstract

Atypical antipsychotic risperidone is widely used first-line monotherapy in schizophrenia and combined therapy in bipolar disorders. Therapeutic plasma concentrations of risperidone and its active moiety are directly influenced by genetic variations in metabolic CYP450 enzymes (CYP2D6 and CYP3A4/5) and transporter (ABCB1) protein and additional environmental factors. Since active metabolite 9-OH risperidone has a greater percentage of the pharmacologically active fraction and is equipotent to the parent drug risperidone, it is assumed that it contributes significantly to therapeutic and adverse effects. Unpredictable dose/concentration ratio, narrow therapeutic index, number of interactions, along with serious adverse reactions (ADR), raises the need for individualization of risperidone treatment and establishing of good therapeutic regime using TDM. A simple and reliable validated bioanalytical liquide-liquide extraction HPLC/UV method was applied for the simultaneous determination of risperidone and its active metabolite, 9-OH risperidone, in human plasma and urine of 52 hospitalized schizophrenia/bipolar disorder patients treated with risperidone as monotherapy and in polytherapy. All the patients were previously genotyped for CYP2D6 (EM=30, EM/IM=14, IM=4 IM/PM=1 and PM=3) and ABCB1 using Real-Time PCR methods with TaqMan SNP genotyping suitable assays according to the guidelines of the manufacturer (Life Technologies, USA).The influence of CYP2D6 phenotype on metabolic ratio MR (Ris/9-OHRis) in plasma (p=0.012) and in urine (p=0.048) was confirmed. Statistically significant correlation (R2=55.53%, Rho=0.844, p<0,0001) for MR in both plasma and urine indicates that urine may be utilized as appropriate media for initial CYP2D6 phenotype identification and selection of patients on risperidone treatment with high risk for ADR.

The influence of CYP enzymes and ABCB1 on treatment outcomes in schizophrenia: association of CYP1A2 activity with adverse effects

“…This does not rule out a true contribution of metabolism or transport on plasma levels. In fact, there have been numerous reports on the association of CYP2D6 with plasma levels of risperidone, aripiprazole, haloperidole, zuclopenthixole, and pimozide [3,6,10,11,13,33,34] and CYP1A2 with olanzapine [35] , which is consistent with their metabolic pathways. For clozapine, the existing data shows a clear association with CYP1A2 activity, including the inducer effect of smoking on plasma levels but the effect of genetic variation itself has failed to show an association in some studies [36][37][38] .…”

“…CYP enzymes can have genetic variation ranging from loss-of-function alleles to full gene duplications, which can have drastic effects on enzymatic activity. The consequences of these variants on the plasma levels of drugs have been extensively reported [3,[10][11][12] . The contribution of ABCB1 to plasma levels has been investigated, although there is little evidence that this transporter plays a relevant role [6,12,13] .…”